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1
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Zhang B, Wu Y, Wang Z, Gao S, Liu H, Lin Y, Yu P. Unveiling macrophage dynamics and efferocytosis-related targets in diabetic kidney disease: insights from single-cell and bulk RNA-sequencing. Front Immunol 2025; 16:1521554. [PMID: 40046045 PMCID: PMC11879818 DOI: 10.3389/fimmu.2025.1521554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/28/2025] [Indexed: 05/13/2025] Open
Abstract
Background Chronic inflammation and immune imbalance mediated by macrophages are considered pivotal in diabetic kidney disease (DKD). The study aims to clarify the macrophage heterogeneity and phenotype dynamics, and pinpoint critical targets within efferocytosis in DKD. Methods Utilizing early human DKD sequencing data, we computed the potential communication between leukocytes and renal intrinsic cells. Subsequently, we scrutinized the single-cell RNA sequencing (scRNA-seq) data from CD45-enriched immune cells, concentrating on the macrophage subsets in DKD. Pseudotime trajectory analysis was conducted to explore cell development. Differential expression genes (DEGs) from macrophage subgroups and bulk RNA-sequencing were used to identify shared hub genes. The NephroseqV5 platform was employed to evaluate the clinical significance, and the expression of key molecules was validated in DKD tissues. Results Macrophage infiltration rose in DKD, causing inflammation through the release of chemokines. As time progressed, the number of resident macrophages substantially dropped, with diminishing M1-like and increasing M2-like phenotypes relative to early stages. Further analysis pointed to the most enrichment of macrophage function is the phagosome. We overlapped the DEGs with efferocytosis-related genes and identified key genes, including CD36, ITGAM, and CX3CR1, which exhibited significant correlations with macrophages and T cells. The Nephroseq database revealed that they are associated with proteinuria and renal function. Consistent with the validation set, in vivo experiments verified elevated expression levels of key molecules. Conclusions In essence, our research elucidated the dynamics in macrophage subtype transitions. It emphasized three pivotal genes as critical modulators of macrophage efferocytosis in DKD, indicating their potential as innovative biomarkers and therapeutic targets.
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Affiliation(s)
- Binshan Zhang
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Yunqi Wu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Zhongli Wang
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Suhua Gao
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Hongyan Liu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Yao Lin
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
| | - Pei Yu
- National Health Commission (NHC) Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, China
- Department of Nephrology & Blood Purification Center, The Second Hospital of Tianjin Medical University, Tianjin, China
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Xie G, Chen X, Gao Y, Yang M, Zhou S, Lu L, Wu H, Lu Q. Age-Associated B Cells in Autoimmune Diseases: Pathogenesis and Clinical Implications. Clin Rev Allergy Immunol 2025; 68:18. [PMID: 39960645 PMCID: PMC11832777 DOI: 10.1007/s12016-025-09021-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2025] [Indexed: 02/20/2025]
Abstract
As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c. Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis. Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.
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Affiliation(s)
- Guangyang Xie
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Xiaojing Chen
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Yixia Gao
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Ming Yang
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Suqing Zhou
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China.
| | - Haijing Wu
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China.
- FuRong Laboratory, Changsha, China.
| | - Qianjin Lu
- Department of Dermatology, the Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, Hunan, China.
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.
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Dai X, Yu J, Zhang Y, Wang Z, Dai Y, Hu Y, Wang X, Tian B, Wu M, Chen H, Song R, Ma D, Wang CY, Ye D, Zheng Z, Zhang L, Luo J, Jing Y. DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B cell activation and differentiation. LIFE MEDICINE 2025; 4:lnaf009. [PMID: 40166629 PMCID: PMC11956853 DOI: 10.1093/lifemedi/lnaf009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/26/2025] [Indexed: 04/02/2025]
Abstract
Systemic lupus erythematosus (SLE) is characterized by the overproduction of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Studies have shown that DNA damage responses play a role in B cell activity in SLE. However, the exact role of DNA damage-induced transcript 3 (DDIT3) in humoral immune response and SLE pathogenesis remains unknown. We observed increased expression of DDIT3 in B cells of SLE patients and this expression was positively correlated with disease activity. In DDIT3-knockout mice, we observed disturbances in B cell development and differentiation, inhibition of B cell activation, and BCR signaling. In addition, DDIT3 deficiency leads to a reduction in T-cell-dependent humoral immune responses. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Finally, we found that DDIT3 deficiency attenuated lupus autoimmunity and reduced germinal center responses. In conclusion, our study reveals for the first time the role of DDIT3 in adaptive immune responses, especially in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for therapeutic intervention in SLE.
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Affiliation(s)
- Xin Dai
- Institute of Clinical Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang 524045, China
| | - Jiali Yu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030009, China
| | - Yunfei Zhang
- Department of Clinical Laboratory, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China
| | - Zhiming Wang
- Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China
| | - Yunyan Dai
- Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China
| | - Ying Hu
- Department of Clinical Laboratory, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China
| | - Xiaocui Wang
- Department of Clinical Laboratory, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 040030, China
| | - Binbin Tian
- Department of Critical Care Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang 524045, China
| | - Minhui Wu
- Institute of Clinical Medicine, Central People’s Hospital of Zhanjiang, Zhanjiang 524045, China
| | - Hao Chen
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
| | - Ruigao Song
- Center of Reproductive Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Dan Ma
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Cong-yi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dawei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ziliang Zheng
- Laboratory of Molecular Imaging, Fifth hospital of Shanxi Medical University (Shanxi Provincial People’s Hospital), Taiyuan 030032, China
| | - Liyun Zhang
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
| | - Jing Luo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan 030009, China
| | - Yukai Jing
- Department of Clinical Laboratory, Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China
- Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China
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Kono DH, Hahn BH. Animal models of systemic lupus erythematosus (SLE). DUBOIS' LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES 2025:189-234. [DOI: 10.1016/b978-0-323-93232-5.00024-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yu J, Gui X, Zou Y, Liu Q, Yang Z, An J, Guo X, Wang K, Guo J, Huang M, Zhou S, Zuo J, Chen Y, Deng L, Yuan G, Li N, Song Y, Jia J, Zeng J, Zhao Y, Liu X, Du X, Liu Y, Wang P, Zhang B, Ding L, Robles AI, Rodriguez H, Zhou H, Shao Z, Wu L, Gao D. A proteogenomic analysis of cervical cancer reveals therapeutic and biological insights. Nat Commun 2024; 15:10114. [PMID: 39578447 PMCID: PMC11584810 DOI: 10.1038/s41467-024-53830-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, genetic alterations, immune infiltration, and post-translational modification regulations. PRKCB is further identified as a potential radioresponse-related biomarker of CC patients. This study provides a valuable public resource for researchers and clinicians to delve into the molecular basis of CC, to identify potential treatments and to ultimately advance clinical practice.
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Affiliation(s)
- Jing Yu
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiuqi Gui
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Yunhao Zou
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qian Liu
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Zhicheng Yang
- University of Chinese Academy of Sciences, Beijing, China
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jusheng An
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuan Guo
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kaihua Wang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiaming Guo
- University of Chinese Academy of Sciences, Beijing, China
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Manni Huang
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuhan Zhou
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jing Zuo
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yimin Chen
- University of Chinese Academy of Sciences, Beijing, China
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Lu Deng
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guangwen Yuan
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Li
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Song
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jia Jia
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jia Zeng
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxi Zhao
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianming Liu
- Bruker (Beijing) Scientific Technology Co., Ltd, Shanghai, China
| | - Xiaoxian Du
- Bruker (Beijing) Scientific Technology Co., Ltd, Shanghai, China
| | - Yansheng Liu
- Department of Pharmacology, Cancer Biology Institute, Yale University School of Medicine, West Haven, CT, USA
| | - Pei Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bing Zhang
- Department of Molecular and Human Genetics, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
| | - Li Ding
- Department of Medicine, McDonnell Genome Institute, Siteman Cancer Center, Washington University, St. Louis, MI, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Hu Zhou
- University of Chinese Academy of Sciences, Beijing, China.
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
| | - Zhen Shao
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Lingying Wu
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Daming Gao
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
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Wang L, Zhu Y, Zhang N, Xian Y, Tang Y, Ye J, Reza F, He G, Wen X, Jiang X. The multiple roles of interferon regulatory factor family in health and disease. Signal Transduct Target Ther 2024; 9:282. [PMID: 39384770 PMCID: PMC11486635 DOI: 10.1038/s41392-024-01980-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/12/2024] [Accepted: 09/10/2024] [Indexed: 10/11/2024] Open
Abstract
Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.
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Affiliation(s)
- Lian Wang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanghui Zhu
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yali Xian
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yu Tang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Ye
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fekrazad Reza
- Radiation Sciences Research Center, Laser Research Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran
- International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Gu He
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiang Wen
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Xian Jiang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Erdő-Bonyár S, Rapp J, Subicz R, Böröcz K, Szinger D, Filipánits K, Minier T, Kumánovics G, Czirják L, Berki T, Simon D. Disturbed Complement Receptor Expression Pattern of B Cells Is Enhanced by Toll-like Receptor CD180 Ligation in Diffuse Cutaneous Systemic Sclerosis. Int J Mol Sci 2024; 25:9230. [PMID: 39273179 PMCID: PMC11394765 DOI: 10.3390/ijms25179230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/23/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Autoantibody production is a hallmark of systemic sclerosis (SSc) and the most extensively studied role of B cells in the pathogenesis of the disease. However, the potential involvement of innate immune molecules in B-cell dysfunction in SSc is less understood. B-cell activation is an early event in the pathogenesis of SSc and is influenced by complement receptors (CRs) and Toll-like receptors (TLRs), shaping antibody responses. CR2 and CR1 modulate B-cell activation, and the roles of CR3 and CR4 are associated with autoimmune conditions. We investigated the expression of CRs in B cells from patients with the more severe form of the disease, diffuse cutaneous SSc (dcSSc), and the effect of TLR CD180 ligation on their expression. We found no significant difference in the basal expression of CD21 and CD11c in B cells between dcSSc and healthy controls (HCs). However, reduced basal CD11b expression in B cells in dcSSc compared to HCs, accompanied by a decrease in CD35 and an increase in CD11c expression following CD180 ligation may promote plasma cell formation and autoantibody production. Additionally, we searched for correlations between dcSSc-associated anti-DNA topoisomerase I (Scl-70) autoantibody, anti-citrate synthase (CS) natural autoantibody and complement component 3 (C3) levels and found a negative correlation between C3 and anti-CS autoantibody in dcSSc but not in HCs, supporting the hypothesis that natural autoantibodies could activate the complement system contributing to tissue injury in SSc.
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Affiliation(s)
- Szabina Erdő-Bonyár
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Judit Rapp
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Rovéna Subicz
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Katalin Böröcz
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Dávid Szinger
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Kristóf Filipánits
- Department of Rheumatology and Immunology, Clinical Center, University of Pécs Medical School, H-7632 Pécs, Hungary
| | - Tünde Minier
- Department of Rheumatology and Immunology, Clinical Center, University of Pécs Medical School, H-7632 Pécs, Hungary
| | - Gábor Kumánovics
- Department of Rheumatology and Immunology, Clinical Center, University of Pécs Medical School, H-7632 Pécs, Hungary
| | - László Czirják
- Department of Rheumatology and Immunology, Clinical Center, University of Pécs Medical School, H-7632 Pécs, Hungary
| | - Tímea Berki
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
| | - Diána Simon
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary
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Wang T, Rathee A, Pemberton PA, Lood C. Exogenous serpin B1 restricts immune complex-mediated NET formation via inhibition of a chymotrypsin-like protease and enhances microbial phagocytosis. J Biol Chem 2024; 300:107533. [PMID: 38971315 PMCID: PMC11327461 DOI: 10.1016/j.jbc.2024.107533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/02/2024] [Accepted: 06/18/2024] [Indexed: 07/08/2024] Open
Abstract
Immune complex (IC)-driven formation of neutrophil extracellular traps (NETs) is a major contributing factor to the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE). Exogenous recombinant human serpin B1 (rhsB1) can regulate NET formation; however, its mechanism(s) of action is currently unknown as is its ability to regulate IC-mediated NET formation and other neutrophil effector functions. To investigate this, we engineered or post-translationally modified rhsB1 proteins that possessed specific neutrophil protease inhibitory activities and pretreated isolated neutrophils with them prior to inducing NET formation with ICs derived from patients with SLE, PMA, or the calcium ionophore A23187. Neutrophil activation and phagocytosis assays were also performed with rhsB1 pretreated and IC-activated neutrophils. rhsB1 dose-dependently inhibited NET formation by all three agents in a process dependent on its chymotrypsin-like inhibitory activity, most likely cathepsin G. Only one variant (rhsB1 C344A) increased surface levels of neutrophil adhesion/activation markers on IC-activated neutrophils and boosted intracellular ROS production. Further, rhsB1 enhanced complement-mediated neutrophil phagocytosis of opsonized bacteria but not ICs. In conclusion, we have identified a novel mechanism of action by which exogenously administered rhsB1 inhibits IC, PMA, and A2138-mediated NET formation. Cathepsin G is a well-known contributor to autoimmune disease but to our knowledge, this is the first report implicating it as a potential driver of NET formation. We identified the rhsB1 C334A variant as a candidate protein that can suppress IC-mediated NET formation, boost microbial phagocytosis, and potentially impact additional neutrophil effector functions including ROS-mediated microbial killing in phagolysosomes.
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Affiliation(s)
- Ting Wang
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Arpit Rathee
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | | | - Christian Lood
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington, USA.
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9
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Li X, Villanueva V, Jimenez V, Nguyen B, Chauhan NR, Khan SQ, Dorschner JM, Jensen MA, Alzahrani K, Wei H, Cimbaluk DJ, Wei DC, Jolly M, Lopez-Rodriguez D, Pineda SB, Barbosa A, Vazquez-Padron RI, Faridi HM, Reiser J, Niewold TB, Gupta V. CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.26.605143. [PMID: 39211173 PMCID: PMC11361177 DOI: 10.1101/2024.07.26.605143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Lupus Nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that affects kidney function. Here, we investigated the role of CD11b, a protein encoded by the ITGAM gene, in the development of LN and its functional activation as a therapeutic strategy. Genetic coding variants of ITGAM significantly increase the risk for SLE and LN by producing a less active CD11b and leading to elevated levels of type I interferon (IFN I). However, a molecular mechanism for how these variants increase LN risk has been unclear. Here, we determined that these variants also significantly associate with elevations in soluble urokinase plasminogen activator receptor (suPAR), a known biomarker linked to kidney disease, suggesting a novel molecular connection. Pharmacologic activation of CD11b with a novel, clinical-stage agonist ONT01 significantly suppressed suPAR production in myeloid cells and reduced systemic inflammation and kidney damage in multiple experimental models of LN. Importantly, delaying treatment with ONT01 until after disease onset also significantly reduced serum suPAR and inflammatory cytokines, and decreased immune complex deposition in the glomerulus, glomerulonephritis and albuminuria, suggesting that CD11b activation is therapeutic for LN. Genetic activation of CD11b via a gain-of-function CD11b mutation also showed complete protection from LN, whereas genetic deletion of CD11b worsened the disease in mice, providing further evidence of the role of CD11b activation in regulating LN. Finally, transfer of human LN PBMCs generated human LN like disease in mice that was significantly reduced by ONT01. Together, these data provide strong evidence that ONT01 mediated CD11b activation can therapeutically modulate TLR7-driven inflammation and protect against LN. These findings support clinical development of CD11b agonists as novel therapeutics for treating lupus nephritis in human patients.
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10
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Eroles M, Lopez-Alonso J, Ortega A, Boudier T, Gharzeddine K, Lafont F, Franz CM, Millet A, Valotteau C, Rico F. Coupled mechanical mapping and interference contrast microscopy reveal viscoelastic and adhesion hallmarks of monocyte differentiation into macrophages. NANOSCALE 2023. [PMID: 37378568 DOI: 10.1039/d3nr00757j] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
Monocytes activated by pro-inflammatory signals adhere to the vascular endothelium and migrate from the bloodstream to the tissue ultimately differentiating into macrophages. Cell mechanics and adhesion play a crucial role in macrophage functions during this inflammatory process. However, how monocytes change their adhesion and mechanical properties upon differentiation into macrophages is still not well understood. In this work, we used various tools to quantify the morphology, adhesion, and viscoelasticity of monocytes and differentiatted macrophages. Combination of atomic force microscopy (AFM) high resolution viscoelastic mapping with interference contrast microscopy (ICM) at the single-cell level revealed viscoelasticity and adhesion hallmarks during monocyte differentiation into macrophages. Quantitative holographic tomography imaging revealed a dramatic increase in cell volume and surface area during monocyte differentiation and the emergence of round and spread macrophage subpopulations. AFM viscoelastic mapping showed important stiffening (increase of the apparent Young's modulus, E0) and solidification (decrease of cell fluidity, β) on differentiated cells that correlated with increased adhesion area. These changes were enhanced in macrophages with a spread phenotype. Remarkably, when adhesion was perturbed, differentiated macrophages remained stiffer and more solid-like than monocytes, suggesting a permanent reorganization of the cytoskeleton. We speculate that the stiffer and more solid-like microvilli and lamellipodia might help macrophages to minimize energy dissipation during mechanosensitive activities. Thus, our results revealed viscoelastic and adhesion hallmarks of monocyte differentiation that may be important for biological function.
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Affiliation(s)
- Mar Eroles
- Aix-Marseille University, INSERM, CNRS, LAI, Turing Centre for Living Systems, Marseille, France.
| | - Javier Lopez-Alonso
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Alexandre Ortega
- Aix-Marseille University, INSERM, CNRS, LAI, Turing Centre for Living Systems, Marseille, France.
| | | | - Khaldoun Gharzeddine
- Univ.Grenoble Alpes, Inserm U1209, CNRS UMR5309, Institute for Advanced Biosciences, Team Mechanobiology, Immunity and Cancer, La Tronche, France
- Department of Hepatogastroenterology, Centre Hospitalier Universitaire de Grenoble Alpes, La Tronche, France
| | - Frank Lafont
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, France
| | - Clemens M Franz
- WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Arnaud Millet
- Univ.Grenoble Alpes, Inserm U1209, CNRS UMR5309, Institute for Advanced Biosciences, Team Mechanobiology, Immunity and Cancer, La Tronche, France
- Department of Hepatogastroenterology, Centre Hospitalier Universitaire de Grenoble Alpes, La Tronche, France
| | - Claire Valotteau
- Aix-Marseille University, INSERM, CNRS, LAI, Turing Centre for Living Systems, Marseille, France.
| | - Felix Rico
- Aix-Marseille University, INSERM, CNRS, LAI, Turing Centre for Living Systems, Marseille, France.
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11
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Liu X, Hogg GD, Zuo C, Borcherding NC, Baer JM, Lander VE, Kang LI, Knolhoff BL, Ahmad F, Osterhout RE, Galkin AV, Bruey JM, Carter LL, Mpoy C, Vij KR, Fields RC, Schwarz JK, Park H, Gupta V, DeNardo DG. Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity. Cancer Cell 2023; 41:1073-1090.e12. [PMID: 37236195 PMCID: PMC10281762 DOI: 10.1016/j.ccell.2023.04.018] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 04/14/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023]
Abstract
Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.
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Affiliation(s)
- Xiuting Liu
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Graham D Hogg
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chong Zuo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Nicholas C Borcherding
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - John M Baer
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Varintra E Lander
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Liang-I Kang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Brett L Knolhoff
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Faiz Ahmad
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | | | | | | | - Cedric Mpoy
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kiran R Vij
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ryan C Fields
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Julie K Schwarz
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Haeseong Park
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Vineet Gupta
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - David G DeNardo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
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12
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Muir V, Sagadiev S, Liu S, Holder U, Armendariz AM, Suchland E, Meitlis I, Camp N, Giltiay N, Tam JM, Garner EC, Wivagg CN, Shows D, James RG, Lacy-Hulbert A, Acharya M. Transcriptomic analysis of pathways associated with ITGAV/alpha(v) integrin-dependent autophagy in human B cells. Autophagy 2023; 19:926-942. [PMID: 36016494 PMCID: PMC9980515 DOI: 10.1080/15548627.2022.2113296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Macroautophagy/autophagy proteins have been linked with the development of immune-mediated diseases including lupus, but the mechanisms for this are unclear due to the complex roles of these proteins in multiple immune cell types. We have previously shown that a form of noncanonical autophagy induced by ITGAV/alpha(v) integrins regulates B cell activation by viral and self-antigens, in mice. Here, we investigate the involvement of this pathway in B cells from human tissues. Our data reveal that autophagy is specifically induced in the germinal center and memory B cell subpopulations of human tonsils and spleens. Transcriptomic analysis show that the induction of autophagy is related to unique aspects of activated B cells such as mitochondrial metabolism. To understand the function of ITGAV/alpha(v) integrin-dependent autophagy in human B cells, we used CRISPR-mediated knockdown of autophagy genes. Integrating data from primary B cells and knockout cells, we found that ITGAV/alpha(v)-dependent autophagy limits activation of specific pathways related to B cell responses, while promoting others. These data provide new mechanistic links for autophagy and B-cell-mediated immune dysregulation in diseases such as lupus.
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Affiliation(s)
- Virginia Muir
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Sara Sagadiev
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Shuozhi Liu
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Ursula Holder
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Andrea M Armendariz
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Emmaline Suchland
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Iana Meitlis
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Nathan Camp
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Natalia Giltiay
- Departments of Rheumatology, University of Washington, Seattle, WA, USA
| | - Jenny M Tam
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.,Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Ethan C Garner
- Department of Molecular and Cell Biology, Harvard University, Cambridge, MA, USA
| | - Carl N Wivagg
- Department of Molecular and Cell Biology, Harvard University, Cambridge, MA, USA
| | - Donna Shows
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Richard G James
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.,Department of Pediatric, University of Washington, Seattle, WA, USA.,Department of Pharmacology, University of Washington, Seattle, WA, USA
| | - Adam Lacy-Hulbert
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,Department of Immunology, University of Washington, Seattle, WA, USA
| | - Mridu Acharya
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.,Department of Pediatric, University of Washington, Seattle, WA, USA
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13
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Yu PC, Hao CY, Fan YZ, Liu D, Qiao YF, Yao JB, Li CZ, Yu Y. Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level. Pharmaceuticals (Basel) 2023; 16:282. [PMID: 37259426 PMCID: PMC9963077 DOI: 10.3390/ph16020282] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/31/2023] [Accepted: 02/08/2023] [Indexed: 11/17/2023] Open
Abstract
Morphine, one of the most efficacious analgesics, is effective in severe pain, especially in patients with concomitant painful cancers. The clinical use of morphine may be accompanied by increased immunosuppression, susceptibility to infection and postoperative tumor metastatic recurrence, and the specific mechanisms and clinical strategies to alleviate this suppression remain to be investigated. Expression of CD11b is closely associated with the macrophage phagocytosis of xenobiotic particles, bacteria or tumor cells. Here, we find that morphine at 0.1-10 nM levels inhibited CD11b expression and function on macrophages via a μ-opioid receptor (MOR)-dependent mechanism, thereby reducing macrophage phagocytosis of tumor cells, a process that can be reversed by thymopentin (TP5), a commonly used immune-enhancing adjuvant in clinical practice. By knocking down or overexpressing MOR on macrophages and using naloxone, an antagonist of the MOR receptor, and LA1, a molecule that promotes macrophage CD11b activation, we suggest that morphine may regulate macrophage phagocytosis by inhibiting the surface expression and function of macrophage CD11b through the membrane expression and activation of MOR. The CD47/SIRPα axis, which is engaged in macrophage-tumor immune escape, was not significantly affected by morphine. Notably, TP5, when combined with morphine, reversed the inhibition of macrophage phagocytosis by morphine through mechanisms that promote membrane expression of CD11b and modulate its downstream signaling (e.g., NOS2, IFNG, IL1B and TNFA, as well as AGR1, PDGFB, IL6, STAT3, and MYC). Thus, altered membrane expression and function of CD11b may mediate the inhibition of macrophage phagocytosis by therapeutic doses of morphine, and the reversal of this process by TP5 may provide an effective palliative option for clinical immunosuppression by morphine.
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Affiliation(s)
- Peng-Cheng Yu
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Cui-Yun Hao
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ying-Zhe Fan
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Di Liu
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yi-Fan Qiao
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Jia-Bao Yao
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Chang-Zhu Li
- State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha 410004, China
| | - Ye Yu
- School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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14
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Siekacz K, Kumor-Kisielewska A, Miłkowska-Dymanowska J, Pietrusińska M, Bartczak K, Majewski S, Stańczyk A, Piotrowski WJ, Białas AJ. Soluble ITGaM and ITGb2 Integrin Subunits Are Involved in Long-Term Pulmonary Complications after COVID-19 Infection. J Clin Med 2023; 12:jcm12010342. [PMID: 36615143 PMCID: PMC9821073 DOI: 10.3390/jcm12010342] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
(1) Introduction: The role of soluble integrins in post-COVID-19 complications is unclear, especially in long-term pulmonary lesions. The purpose of this study was to investigate the association between soluble ITGa2, ITGaM and ITGb2 integrin subunits and long COVID-19 pulmonary complications. (2) Methodology: Post-COVID-19 patients were enrolled. According to the evidence of persistent interstitial lung lesions on CT, patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(-)). We randomly selected 80 patients for further investigation (40 subjects for each group). Levels of ITGa2, ITGaM and ITGb2 integrin subunits were determined by ELISA assay. (3) Results: The serum concentration of sITGaM and sITGb2 were significantly higher in the P(+) group (sITGaM 18.63 ng/mL [IQR 14.17-28.83] vs. 14.75 ng/mL [IQR 10.91-20] p = 0.01 and sITGb2 10.55 ng/mL [IQR 6.53-15.83] vs. 6.34 ng/mL [IQR 4.98-9.68] p = 0.002). We observed a statistically significant correlation between sITGaM and sITGb2 elevation in the P(+) group (R = 0.42; p = 0.01). Patients from the P(+) group had a lower (1.82 +/-0.84 G/L) lymphocyte level than the P(-)group (2.28 +/-0.79 G/L), p = 0.03. Furthermore, we observed an inverse correlation in the P(-) group between blood lymphocyte count and sITGb2 integrin subunit levels (R = -0.49 p = 0.01). (4) Conclusions: Elevated concentrations of sITGaM and sITGb2 were associated with long-term pulmonary complications in post-COVID-19 patients. Both sITGaM and sITGb2 may be promising biomarkers for predicting pulmonary complications and could be a potential target for therapeutic intervention in post-COVID-19 patients.
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Affiliation(s)
- Kamil Siekacz
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland
| | | | | | | | - Krystian Bartczak
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Sebastian Majewski
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland
| | - Adam Stańczyk
- Department of Clinical Pharmacology, Medical University of Lodz, 90-419 Lodz, Poland
| | | | - Adam J. Białas
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland
- Department of Pulmonary Rehabilitation, Regional Medical Center for Lung Diseases and Rehabilitation, 91-520 Lodz, Poland
- Correspondence:
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15
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Ye H, Li L, Dong Y, Zheng Q, Sha Y, Li L, Yang P, Jia Y, Gu J. Dysregulated low-density granulocyte contributes to early spontaneous abortion. Front Immunol 2023; 14:1119756. [PMID: 36911722 PMCID: PMC9995479 DOI: 10.3389/fimmu.2023.1119756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Spontaneous abortion (SA) is a common adverse pregnancy event with unclarified pathogenesis and limited therapeutic efficiency. Although most SA cases with the euploid embryo(s) are associated with immunological factors, the contribution of low-density granulocyte (LDG) in SA pathogenesis is rarely reported. This study aimed to investigate the serial characteristics and possible contribution of LDG and their subpopulations in early pregnancy, especially in early SA. Unpregnant (UP), normally pregnant (NP), and SA women were recruited, and the peripheral blood and endometrium/decidua were collected for LDG isolation and histological observation. The percentage, phenotype, and subpopulations of LDG were analyzed via flow cytometric analysis, and the ability of Nets formation was assessed by immunofluorescent and immunohistochemical assays. As a result, 43 participants were enrolled, including 10 UP, 15 NP, and 18 SA women. Compared with the UP group, the LDG percentage in peripheral blood mononuclear cells (PBMCs) and decidual immune cells (DICs) increased in the NP group, while the loss of this increase was observed in the SA group. Meanwhile, CD16int/- cell percentage in peripheral blood LDG (PB-LDG) increased in the NP and SA groups, and insufficient activation of CD16hi PB-LDG characterized by reduced CD11b expression was discovered in the SA group. Moreover, the LDG percentage in DICs was higher than that in PBMCs, and the decidual LDG (D-LDG) showed a surface marker expression profile that is easier to be activated in the pregnant cohort (NP + SA women). Finally, increased decidual Nets formation was observed in the SA group compared with the NP group, and more Nets formation was detected in D-LDG of NP and SA women following PMA stimulation. Overall, LDG participates in the maintenance of early pregnancy, while dysregulated LDG is responsible for early SA, providing novel potential targets for further exploration of SA pathogenesis and therapeutics.
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Affiliation(s)
- Hongxia Ye
- Department of Reproductive Immunology, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
- Department of Reproductive Immunology, Chengdu Jinjiang Hospital for Maternal & Child Health Care, Chengdu, Sichuan, China
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yajun Dong
- Department of Reproductive Immunology, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
| | - Qu Zheng
- Department of Laboratory Medicine, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
| | - Yulin Sha
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
| | - Li Li
- Department of Gynecology, Sichuan Jinxin Women & Children Hospital, Chengdu, Sichuan, China
| | - Panyu Yang
- Department of Laboratory Medicine, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
| | - Yan Jia
- Department of Reproductive Immunology, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
- *Correspondence: Yan Jia, ; Jiang Gu,
| | - Jiang Gu
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Xi’nan Gynecology Hospital, Chengdu, Sichuan, China
- Department of Pathology and Pathophysiology, Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Shantou University Medical College, Shantou, China
- *Correspondence: Yan Jia, ; Jiang Gu,
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16
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Filipović M, Flegar D, Aničić S, Šisl D, Kelava T, Kovačić N, Šućur A, Grčević D. Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2 hi osteoclast progenitors. Front Immunol 2022; 13:994035. [PMID: 36591261 PMCID: PMC9797520 DOI: 10.3389/fimmu.2022.994035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction The existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior. Methods In order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation. Results A disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis. Conclusion Our approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.
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Affiliation(s)
- Maša Filipović
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Darja Flegar
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sara Aničić
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Dino Šisl
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Tomislav Kelava
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Nataša Kovačić
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alan Šućur
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
| | - Danka Grčević
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
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17
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Li L, Duan X, Wang H, Sun Y, Zhao W, Lu Y, Xu H, You Y, Wang Q. Is cell regeneration and infiltration a double edged sword for porcine aortic valve deterioration? A large cohort of histopathological analysis. BMC Cardiovasc Disord 2022; 22:336. [PMID: 35902792 PMCID: PMC9335994 DOI: 10.1186/s12872-022-02776-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 07/12/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Bioprostheses are the most common prostheses used for valve replacement in the Western medicine. The major flaw of bioprostheses is the occurrence of structural valve deterioration (SVD). This study aimed to assess the pathological features of porcine aortic valve (PAV)-SVD based on histomorphological and immunopathological characteristics of a large cohort of patients. METHODS Histopathological data of 109 cases with resected PAV were collected. The type and amount of infiltrated cells were evaluated in the different types of bioprosthetic SVD by immunohistochemical staining. RESULTS The most common cause of SVD was calcification, leaflet tear, and dehiscence (23.9%, 19.3%, and 18.3%, respectively). Immunohistochemical staining demonstrated that macrophages were infiltrated in the calcified, lacerated and dehiscence PAV, in which both M1 and M2 macrophages were existed in the calcified PAV. Importantly, the higher content of M1 macrophages and less content of M2 macrophages were found in the lacerated and dehiscence PAV, and MMP-1 expression was mainly found in the lacerated PAV. The endothelialization rate of leaflet dehiscence was higher than that of calcified and lacerated leaflets. A large number of CD31+/CD11b+ cells was aggregated in the spongy layer in the lacerated and dehiscence PAV. CONCLUSION Cell regeneration and infiltration is a double edged sword for the PAV deterioration. Macrophage infiltration is involved in the different types of SVD, while only MMP-1 expression is involved in lacerated leaflets. The macrophage subtype of circulating angiogenic cells in dehiscence and tear PAV could be identified, which could reserve macrophages in the PAV-SVD.
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Affiliation(s)
- Li Li
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China.
| | - Xuejing Duan
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Hongyue Wang
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Yang Sun
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Wei Zhao
- Center for Adult Surgery, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Yang Lu
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Hongyu Xu
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Yiwei You
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
| | - Qingzhi Wang
- Department of Pathology, Fuwai Hospital, Peking UnionMedical College, Chinese Academy of Medical Science, Beilishi Road No. 167, Xicheng District, Beijing, 100037, China
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18
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Querrey M, Chiu S, Lecuona E, Wu Q, Sun H, Anderson M, Kelly M, Ravi S, Misharin AV, Kreisel D, Bharat A, Budinger GS. CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation. J Clin Invest 2022; 132:157262. [PMID: 35838047 PMCID: PMC9282933 DOI: 10.1172/jci157262] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/25/2022] [Indexed: 02/03/2023] Open
Abstract
Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damage-associated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients.
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Affiliation(s)
- Melissa Querrey
- Division of Pulmonary and Critical Care Medicine and,Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Stephen Chiu
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Emilia Lecuona
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Qiang Wu
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Haiying Sun
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Megan Anderson
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Megan Kelly
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Sowmya Ravi
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | | | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Ankit Bharat
- Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - G.R. Scott Budinger
- Division of Pulmonary and Critical Care Medicine and,Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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19
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Villanueva V, Li X, Jimenez V, Faridi HM, Gupta V. CD11b agonists offer a novel approach for treating lupus nephritis. Transl Res 2022; 245:41-54. [PMID: 35288363 PMCID: PMC9167730 DOI: 10.1016/j.trsl.2022.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/20/2022]
Abstract
Lupus nephritis (LN) develops in more than a third of all systemic lupus erythematosus (SLE) patients and is the strongest predictor of morbidity and mortality. Increased circulating levels of type I interferon (IFN I) and anti-double stranded DNA (anti-dsDNA) and anti-RNA binding protein (anti-RNP) antibodies lead to increased glomerular injury via leukocyte activation and glomerular infiltration. Uncontrolled Toll-like receptor (TLR) signaling in leukocytes results in increased production of IFN I and anti-dsDNA antibodies. ITGAM gene codes for integrin CD11b, the α-chain of integrin heterodimer CD11b/CD18, that is highly expressed in leukocytes and modulates TLR-dependent pro-inflammatory signaling. Three nonsynonymous SNPs in the ITGAM gene strongly correlate with increased risk for SLE and LN and with IFN I levels. Here we review the literature on the role of CD11b on leukocytes in LN. We also incorporate conclusions from several recent studies that show that these ITGAM SNPs result in a CD11b protein that is less able to suppress TLR-dependent pro-inflammatory pathways in leukocytes, that activation of CD11b via novel small molecule agonists suppresses TLR-dependent pathways, including reductions in circulating levels of IFN I and anti-dsDNA antibodies, and that CD11b activation reduces LN in model systems. Recent data strongly suggest that integrin CD11b is an exciting new therapeutic target in SLE and LN and that allosteric activation of CD11b is a novel therapeutic paradigm for effectively treating such autoimmune diseases.
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Affiliation(s)
- Veronica Villanueva
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Xiaobo Li
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Viviana Jimenez
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Hafeez M Faridi
- Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, Chicago, Illinois
| | - Vineet Gupta
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
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20
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Dendritic cells in systemic lupus erythematosus: From pathogenesis to therapeutic applications. J Autoimmun 2022; 132:102856. [DOI: 10.1016/j.jaut.2022.102856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022]
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21
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Gottschalk TA, Hall P, Tsantikos E, L’Estrange-Stranieri E, Hickey MJ, Hibbs ML. Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking. Front Immunol 2022; 13:875359. [PMID: 35634296 PMCID: PMC9134083 DOI: 10.3389/fimmu.2022.875359] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/19/2022] [Indexed: 11/26/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. A common manifestation, lupus nephritis, arises from immune complex deposition in the kidney microvasculature promoting leukocyte activation and infiltration, which triggers glomerular damage and renal dysfunction. CD11b is a leukocyte integrin mainly expressed on myeloid cells, and aside from its well-ascribed roles in leukocyte trafficking and phagocytosis, it can also suppress cytokine production and autoreactivity. Genome-wide association studies have identified loss-of-function polymorphisms in the CD11b-encoding gene ITGAM that are strongly associated with SLE and lupus nephritis; however, it is not known whether these polymorphisms act alone to induce disease or in concert with other risk alleles. Herein we show using Itgam-/- mice that loss of CD11b led to mild inflammatory traits, which were insufficient to trigger autoimmunity or glomerulonephritis. However, deficiency of CD11b in autoimmune-prone Lyn-deficient mice (Lyn-/-Itgam-/-) accelerated lupus-like disease, driving early-onset immune cell dysregulation, autoantibody production and glomerulonephritis, impacting survival. Migration of leukocytes to the kidney in Lyn-/- mice was unhindered by lack of CD11b. Indeed, kidney inflammatory macrophages were further enriched, neutrophil retention in glomerular capillaries was increased and kidney inflammatory cytokine responses were enhanced in Lyn-/-Itgam-/- mice. These findings indicate that ITGAM is a non-monogenic autoimmune susceptibility gene, with loss of functional CD11b exacerbating disease without impeding glomerular leukocyte trafficking when in conjunction with other pre-disposing genetic mutations. This highlights a primarily protective role for CD11b in restraining inflammation and autoimmune disease and provides a potential therapeutic avenue for lupus treatment.
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Affiliation(s)
- Timothy A. Gottschalk
- Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Pamela Hall
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Evelyn Tsantikos
- Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Elan L’Estrange-Stranieri
- Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Michael J. Hickey
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Margaret L. Hibbs
- Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- *Correspondence: Margaret L. Hibbs,
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22
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Ma Y, Chen J, Wang T, Zhang L, Xu X, Qiu Y, Xiang AP, Huang W. Accurate Machine Learning Model to Diagnose Chronic Autoimmune Diseases Utilizing Information From B Cells and Monocytes. Front Immunol 2022; 13:870531. [PMID: 35515003 PMCID: PMC9065417 DOI: 10.3389/fimmu.2022.870531] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/22/2022] [Indexed: 12/17/2022] Open
Abstract
Heterogeneity and limited comprehension of chronic autoimmune disease pathophysiology cause accurate diagnosis a challenging process. With the increasing resources of single-cell sequencing data, a reasonable way could be found to address this issue. In our study, with the use of large-scale public single-cell RNA sequencing (scRNA-seq) data, analysis of dataset integration (3.1 × 105 PBMCs from fifteen SLE patients and eight healthy donors) and cellular cross talking (3.8 × 105 PBMCs from twenty-eight SLE patients and eight healthy donors) were performed to identify the most crucial information characterizing SLE. Our findings revealed that the interactions among the PBMC subpopulations of SLE patients may be weakened under the inflammatory microenvironment, which could result in abnormal emergences or variations in signaling patterns within PBMCs. In particular, the alterations of B cells and monocytes may be the most significant findings. Utilizing this powerful information, an efficient mathematical model of unbiased random forest machine learning was established to distinguish SLE patients from healthy donors via not only scRNA-seq data but also bulk RNA-seq data. Surprisingly, our mathematical model could also accurately identify patients with rheumatoid arthritis and multiple sclerosis, not just SLE, via bulk RNA-seq data (derived from 688 samples). Since the variations in PBMCs should predate the clinical manifestations of these diseases, our machine learning model may be feasible to develop into an efficient tool for accurate diagnosis of chronic autoimmune diseases.
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Affiliation(s)
- Yuanchen Ma
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Jieying Chen
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Tao Wang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Liting Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Xinhao Xu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuxuan Qiu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Weijun Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Weijun Huang,
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23
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Wang S, Zaitoun IS, Darjatmoko SR, Sheibani N, Sorenson CM. Bim Expression Promotes the Clearance of Mononuclear Phagocytes during Choroidal Neovascularization, Mitigating Scar Formation in Mice. Life (Basel) 2022; 12:208. [PMID: 35207495 PMCID: PMC8878746 DOI: 10.3390/life12020208] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is increasingly recognized as an important modulator in the pathogenesis of neovascular age-related macular degeneration (nAMD). Although significant progress has been made in delineating the pathways that contribute to the recruitment of inflammatory cells and their contribution to nAMD, we know little about what drives the resolution of these inflammatory responses. Gaining a better understanding of how immune cells are cleared in the choroid will give a novel insight into how sustained inflammation could influence the pathogenesis of nAMD. The pro-apoptotic Bcl-2 family member Bim is a master regulator of immune cell homeostasis. In its absence, immune cell lifespan and numbers increase. Most therapeutic regimes that squelch inflammation do so by enhancing immune cell apoptosis through enhanced Bim expression and activity. To test the hypothesis that Bim expression tempers inflammation during the pathogenesis of nAMD, we used the mouse laser-induced choroidal neovascularization (CNV) model in which inflammation acts as a facilitator of CNV. Here, we showed minimal to no change in the recruitment of F4/80-, CD80-, CD11b-, and Iba1-positive myeloid-derived mononuclear phagocytes to the site of laser photocoagulation in the absence of Bim expression. However, the resolution of these cells from the choroid of Bim-deficient (Bim -/-) mice was significantly diminished following laser photocoagulation. With time, we noted increased scar formation, demonstrated by collagen I staining, in Bim -/- mice with no change in the resolution of neovascularization compared to wild-type littermates. We also noted that mice lacking Bim expression in mononuclear phagocytes (BimFlox/Flox; Lyz2-Cre (BimMP) mice) had delayed resolution of F4/80-, CD80-, CD11b-, and Iba1-positive cells, while those lacking Bim expression in endothelial cells (BimFlox/Flox; Cad5-Cre (BimEC) mice) had delayed resolution of only CD11b- and Iba1-positive cells. Both BimMP and BimEC mice demonstrated increased scar formation, albeit to differing degrees. Thus, our studies show that resolving inflammation plays an important role in moderating scar formation in nAMD, and it is impacted by Bim expression in both the endothelium and mononuclear phagocyte lineages.
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Affiliation(s)
- Shoujian Wang
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.W.); (I.S.Z.); (S.R.D.); (N.S.)
| | - Ismail S. Zaitoun
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.W.); (I.S.Z.); (S.R.D.); (N.S.)
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Soesiawati R. Darjatmoko
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.W.); (I.S.Z.); (S.R.D.); (N.S.)
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (S.W.); (I.S.Z.); (S.R.D.); (N.S.)
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Christine M. Sorenson
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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24
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Qiu W, Yu T, Deng GM. The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus. Front Immunol 2022; 13:924766. [PMID: 36311714 PMCID: PMC9609414 DOI: 10.3389/fimmu.2022.924766] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE), often known simply as lupus, is a severe chronic autoimmune disease that is characterized by multi-organ and tissue damage and high levels of autoantibodies in serum. We have recently investigated, using animal models, the role of organ-deposited IgG autoantibodies in the pathogenesis of organ and tissue damage in SLE. We found that intra-organ injection of serum from mice with lupus (i.e., lupus mice) into healthy mice triggered inflammation in tissue and organs but that serum from other healthy mice did not, and that the severity of inflammation was related to the dose of serum injected. Immunohistochemistry showed that a large number of IgG molecules are deposited at the site of organ and tissue damage in lupus mice, and that IgG is a major contributor to the development of tissue inflammation triggered by serum from lupus mice or patients. The development of tissue inflammation induced by IgG in serum from lupus mice requires the presence of monocytes/macrophages, but not of lymphocytes or neutrophils; tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) and interleukin 1 (IL-1) also play essential roles in the development of tissue inflammation triggered by IgG. In addition, it has been found that TNFR1 inhibitors can suppress skin injury in lupus mice and that spleen tyrosine kinase (Syk) inhibitors, which can block the signaling transduction of IgG/Fc gamma receptors (FcγRs), can prevent and treat skin injury and kidney damage in lupus mice. We have also observed that lupus IgG might protect against bone erosion. Based on these results, we conclude that IgG plays a crucial role in the development of organ and tissue damage in SLE and in protecting bone erosion and arthritis, and we suggest that the IgG/FcγR signaling pathway is an important therapeutic target in SLE.
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25
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Gao P, Adachi T, Okai S, Morita N, Kitamura D, Shinkura R. Integrin CD11b provides a new marker of pre-germinal center IgA + B cells in murine Peyer's patches. Int Immunol 2021; 34:249-262. [PMID: 34971392 PMCID: PMC9020567 DOI: 10.1093/intimm/dxab113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/30/2021] [Indexed: 11/15/2022] Open
Abstract
Activated B cells can enter germinal centers (GCs) for affinity maturation to produce high-affinity antibodies. However, which activated B cells will enter GCs remains unknown. Here, we found a small population of CD11b+IgA+ B cells located outside of GCs in murine Peyer’s patches (PPs). After injection of the CD11b+IgA+ PP B cells into a PP of a recipient mouse, they entered GCs forty hours later. They expressed GC surface markers and pre-GC B cell genes, suggesting that CD11b provides a novel surface marker of pre-GC IgA+ B cells in murine PPs. Furthermore, independently of dendritic cell activation, CD11b expression on B cells can be induced by bacterial antigens, such as pam3CSK4 and heat-killed Escherichia coli in vitro. In addition, mice orally administered with pam3CSK4 or heat-killed E. coli increased the number of PP GC B cells within two days, and enhanced the mucosal antigen-specific IgA response. Our results demonstrate that the induction of CD11b on B cells is a promising marker for selecting an effective mucosal vaccine adjuvant.
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Affiliation(s)
- Peng Gao
- Institute for Quantitative Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
- Graduate School of Frontier Science, University of Tokyo, Kashiwa-shi, Chiba 277-8561, Japan
| | - Takahiro Adachi
- Department of Precision Health, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Shinsaku Okai
- Department of Applied Immunology, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
| | - Naoki Morita
- Institute for Quantitative Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Daisuke Kitamura
- Division of Cancer Biology, Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science, Noda, Chiba 278-0022, Japan
| | - Reiko Shinkura
- Institute for Quantitative Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
- Graduate School of Frontier Science, University of Tokyo, Kashiwa-shi, Chiba 277-8561, Japan
- Collaborative Research Institute for Innovative Microbiology, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan
- Correspondence to: R. Shinkura; E-mail:
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Ghodke-Puranik Y, Jin Z, Zimmerman KD, Ainsworth HC, Fan W, Jensen MA, Dorschner JM, Vsetecka DM, Amin S, Makol A, Ernste F, Osborn T, Moder K, Chowdhary V, Langefeld CD, Niewold TB. Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes. Arthritis Res Ther 2021; 23:290. [PMID: 34847931 PMCID: PMC8630910 DOI: 10.1186/s13075-021-02660-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 10/17/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.
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Affiliation(s)
- Yogita Ghodke-Puranik
- Colton Center for Autoimmunity, NYU Grossman School of Medicine, 550 1st Ave, New York, NY, 10016, USA
| | - Zhongbo Jin
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Kip D Zimmerman
- Department of Biostatistics and Data Science and Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Hannah C Ainsworth
- Department of Biostatistics and Data Science and Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Wei Fan
- Department of Rheumatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mark A Jensen
- Colton Center for Autoimmunity, NYU Grossman School of Medicine, 550 1st Ave, New York, NY, 10016, USA
| | - Jessica M Dorschner
- Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | - Danielle M Vsetecka
- Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | - Shreyasee Amin
- Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | - Ashima Makol
- Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | | | - Thomas Osborn
- Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | - Kevin Moder
- Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
| | - Vaidehi Chowdhary
- Division of Rheumatology, Allergy and Immunology, Yale University School of Medicine, New Haven, USA
| | - Carl D Langefeld
- Department of Biostatistics and Data Science and Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Timothy B Niewold
- Colton Center for Autoimmunity, NYU Grossman School of Medicine, 550 1st Ave, New York, NY, 10016, USA.
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27
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Sobieszek G, Mlak R, Powrózek T, Mazurek M, Skwarek-Dziekanowska A, Terlecki P, Małecka-Massalska T. Polymorphism of the ITGAM gene (rs7193943) and bioelectric impedance analysis as potential predictors of cachexia in chronic heart failure. Sci Rep 2021; 11:20145. [PMID: 34635743 PMCID: PMC8505625 DOI: 10.1038/s41598-021-99719-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/24/2021] [Indexed: 12/27/2022] Open
Abstract
Cardiac cachexia (CC) is an unfavorable metabolic syndrome leading to exacerbation of chronic heart failure (CHF) and a higher risk of death. The main factor contributing to the development of cachexia is the ongoing inflammatory process mediated by genes (e.g. Integrin Subunit Alpha M-ITGAM). The study aimed to assess the relationship between a single nucleotide polymorphism (SNP) -323G > A of the ITGAM and the occurrence of nutritional disorders in patients with CHF. 157 CHF patients underwent clinical and nutritional screening. Body composition was evaluated by bioelectrical impedance analysis (BIA). Patients with cachexia were characterized by significantly lower weight, body mass index (BMI), lower fat mass (FM), albumin, and hemoglobin. Lower values of BIA parameters: capacitance of membrane (Cm), phase angle (PA), and impedance ratio (Z200/Z5) were noted in women. Those patients demonstrated significantly higher values of creatinine, c-reactive protein (CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and pulmonary artery systolic pressure (PASP). A significantly higher risk of cachexia was reported in patients: aged ≥ 74 years (OR 3.55), with renal failure (OR 3.75), New York Heart Association classification (NYHA) III-IV (OR 2.83), with moderate or severe malnutrition according to the score of subjective global assessment (SGA) (OR 19.01) and AA genotype of ITGAM gene (OR 2.03). Determination of the -323G > A SNP in the ITGAM may prove to be a useful marker (after confirmation in further studies and appropriate validation) in the assessment of the risk of nutritional disorders in patients with CHF.
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Affiliation(s)
- Grzegorz Sobieszek
- Department of Cardiology, 1St Military Clinical Hospital with the Outpatient Clinic, al. Racławickie 23, 20-048, Lublin, Poland.
| | - Radosław Mlak
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland.
| | - Tomasz Powrózek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Marcin Mazurek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Aneta Skwarek-Dziekanowska
- Department of Cardiology, 1St Military Clinical Hospital with the Outpatient Clinic, al. Racławickie 23, 20-048, Lublin, Poland
| | - Piotr Terlecki
- Department of Vascular Surgery and Angiology, Medical University of Lublin, Lublin, Poland
| | - Teresa Małecka-Massalska
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
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DeNardo DG, Galkin A, Dupont J, Zhou L, Bendell J. GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors. J Immunother Cancer 2021; 9:jitc-2021-003005. [PMID: 34452928 PMCID: PMC8404448 DOI: 10.1136/jitc-2021-003005] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 12/20/2022] Open
Abstract
Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; αMβ2), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.
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Affiliation(s)
- David G DeNardo
- Department of Medicine, ICCE Institute, Department of Pathology and Immunology, Siteman Cancer Center, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | | | | | - Lei Zhou
- Gossamer Bio, San Diego, California, USA
| | - Johanna Bendell
- Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee, USA
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29
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Zhang X, Yang Y, Jing L, Zhai W, Zhang H, Ma Q, Li C, Yan F, Cheng D, Zhang J, Ning Z, Shi H, Wang C, Zhao M, Dai J, Li Z, Ming J, Yu M, Wang H, Cheng H, Xiong H, Dong G. Pyruvate Kinase M2 Contributes to TLR-Mediated Inflammation and Autoimmunity by Promoting Pyk2 Activation. Front Immunol 2021; 12:680068. [PMID: 34025679 PMCID: PMC8138060 DOI: 10.3389/fimmu.2021.680068] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/22/2021] [Indexed: 11/13/2022] Open
Abstract
Toll-like receptors (TLRs) play critical roles in regulating the abnormal activation of the immune cells resulting in the pathogenesis of inflammation and autoimmune diseases. Pyruvate kinase M2 (PKM2), which governs the last step of glycolysis, is involved in multiple cellular processes and pathological conditions. However, little is known about the involvement of PKM2 in regulating TLR-mediated inflammation and autoimmunity. Herein, we investigated the role of PKM2 in the activation of the TLR pathways and the pathogenesis of inflammation and autoimmune diseases. The activation of TLR4, TLR7 and TLR9 pathways was found to induce the up-regulation of PKM2 expression in macrophages, dendritic cells (DCs) and B cells. The over-expression of PKM2 promotes the activation of TLR4, TLR7 and TLR9 pathways while interference with the PKM2 expression or the addition of the PKM2 inhibitor (PKM-IN) markedly inhibited the activation of TLR4, TLR7 and TLR9 pathways. Mechanistically, PKM2 augmented the activation of TLR4, TLR7 and TLR9 pathways by promoting the activation of the proline-rich tyrosine kinase 2 (Pyk2). Intriguingly, the PKM2 inhibitor PKM2-IN significantly protected the mice from the endotoxic shock mediated by the TLR4-agonist LPS. Additionally, it alleviated the progression in the TLR7-agonist imiquimod-mediated lupus mice and spontaneous lupus MRL/lpr mice. Moreover, PKM2 expression was highly elevated in the monocytes, DCs and B cells from systemic lupus erythematous (SLE) patients compared with those from the healthy donors. Besides, the PKM2 expression level was positively correlated with the degree of activation of these immune cells. In summary, PKM2 contributed to TLR-mediated inflammation and autoimmunity and can be a valuable target to control inflammation and autoimmunity.
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Affiliation(s)
- Xin Zhang
- School of Medical Laboratory, Weifang Medical University, Weifang, China
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, China
| | - Lina Jing
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weiwei Zhai
- Department of Clinical Laboratory, Jining No. 1 People’s Hospital, Jining, China
| | - Hui Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Qun Ma
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Chunxia Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Fenglian Yan
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Dalei Cheng
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junfeng Zhang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Zhaochen Ning
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Hui Shi
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Changying Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Mingsheng Zhao
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Jun Dai
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Zhihua Li
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Jiankuo Ming
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Meimei Yu
- School of Medical Laboratory, Weifang Medical University, Weifang, China
| | - Haiyan Wang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hongyan Cheng
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
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Lamers C, Plüss CJ, Ricklin D. The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology. Front Immunol 2021; 12:662164. [PMID: 33995387 PMCID: PMC8118671 DOI: 10.3389/fimmu.2021.662164] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/12/2021] [Indexed: 12/19/2022] Open
Abstract
The β2-integrin receptor family has a broad spectrum of physiological functions ranging from leukocyte adhesion, cell migration, activation, and communication to the phagocytic uptake of cells and particles. Among the members of this family, complement receptor 3 (CR3; CD11b/CD18, Mac-1, αMβ2) is particularly promiscuous in its functional profile and ligand selectivity. There are close to 100 reported structurally unrelated ligands for CR3, and while many ligands appear to cluster at the αMI domain, molecular details about binding modes remain largely elusive. The versatility of CR3 is reflected in its functional portfolio, which includes prominent roles in the removal of invaders and cell debris, induction of tolerance and synaptic pruning, and involvement in the pathogenesis of numerous autoimmune and chronic inflammatory pathologies. While CR3 is an interesting therapeutic target for immune modulation due to these known pathophysiological associations, drug development efforts are limited by concerns of potential interference with host defense functions and, most importantly, an insufficient molecular understanding of the interplay between ligand binding and functional impact. Here, we provide a systematic summary of the various interaction partners of CR3 with a focus on binding mechanisms and functional implications. We also discuss the roles of CR3 as an immune receptor in health and disease, as an activation marker in research and diagnostics, and as a therapeutic target.
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Affiliation(s)
- Christina Lamers
- Molecular Pharmacy Unit, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
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31
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Ding X, Ren Y, He X. IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis. Front Immunol 2021; 12:676082. [PMID: 33959133 PMCID: PMC8093624 DOI: 10.3389/fimmu.2021.676082] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/06/2021] [Indexed: 12/13/2022] Open
Abstract
Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.
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Affiliation(s)
- Xuewei Ding
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Ren
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Pediatric Internal Medicine Department, Haikou Maternal and Child Health Hospital, Haikou, China
| | - Xiaojie He
- Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China.,Laboratory of Pediatric Nephrology, Institute of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, China
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32
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Characterization of innate and adaptive immune cells involved in the foreign body reaction to polypropylene meshes in the human abdomen. Hernia 2021; 26:309-323. [PMID: 33788008 PMCID: PMC8881270 DOI: 10.1007/s10029-021-02396-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/10/2021] [Indexed: 12/25/2022]
Abstract
Background Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells, namely T cells, have also been regularly observed, which appear to play a crucial role in the long-term host response. Methods This study investigated the FBR to seven human PP meshes, which were removed from the abdomen for recurrence after a median of one year. Using immunofluorescence microscopy, the FBR was examined for various innate (CD11b+ myeloid, CD68+ macrophages, CD56+ NK) and adaptive immune cells (CD3+ T, CD4+ T-helper, CD8+ cytotoxic, FoxP3+ T-regulatory, CD20+ B) as well as “conventional” immune cells (defined as cells expressing their specific immune cell marker without co-expressing CD68). Results T-helper cells (19%) and regulatory T-cells (25%) were present at comparable rates to macrophages, and clustered significantly toward the mesh fibers. For all cell types the lowest proportions of “conventional” cells (< 60%) were observed at the mesh–tissue interface, but increased considerably at about 50–100 µm, indicating reduced stimulation with rising distance to the mesh fibers. Conclusion Both innate and adaptive immune cells participate in the chronic FBR to PP meshes with T cells and macrophages being the predominant cell types, respectively. In concordance with the previous data, many cells presented a “hybrid” pattern near the mesh fibers. The complexity of the immune reaction seen within the foreign body granuloma may explain why approaches focusing on specific cell types have not been very successful in reducing the chronic FBR. Supplementary Information The online version contains supplementary material available at 10.1007/s10029-021-02396-7.
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33
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Zhou M, Wang X, Shi Y, Ding Y, Li X, Xie T, Shi Z, Fu W. Deficiency of ITGAM Attenuates Experimental Abdominal Aortic Aneurysm in Mice. J Am Heart Assoc 2021; 10:e019900. [PMID: 33749307 PMCID: PMC8174368 DOI: 10.1161/jaha.120.019900] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background Integrin αM (CD11b), which is encoded by the Integrin Subunit Alpha M (ITGAM) gene, is not only a surface marker of monocytes but also an essential adhesion molecule. In this study, we investigated the effect of CD11b on experimental abdominal aortic aneurysm and the potential underlying mechanisms. Methods and Results The incidence of abdominal aortic aneurysm was not significantly lower in ITGAM(‐/‐) mice than in control mice. Nevertheless, knockout of CD11b reduced the maximum abdominal aortic diameter, macrophage infiltration, matrix metalloproteinase‐9 expression, and elastin and collagen degradation. Additionally, lower expression of IL‐6 was found in both the peripheral blood and abdominal aortas of ITGAM(‐/‐) mice, indicating a biological correlation between CD11b and the inflammatory response in abdominal aortic aneurysm. In vitro, the number of ITGAM(‐/‐) bone marrow–derived macrophages (BMDMs) that adhered to endothelial cells was significantly lower than the number of wild‐type BMDMs. Moreover, the CD11b monoclonal antibody and CD11b agonist leukadherin‐1 decreased and increased the number of adherent wild‐type BMDMs, respectively. Through RNA sequencing, genes associated with leukocyte transendothelial migration were found to be downregulated in ITGAM(‐/‐) BMDMs. Furthermore, immunoprecipitation–mass spectrometry analysis predicted that the Akt pathway might be responsible for the impaired transmigratory ability of ITGAM(‐/‐) BMDMs. The reduced activation of Akt was then confirmed, and the Akt agonist SC79 partially rescued the transendothelial migratory function of ITGAM(‐/‐) BMDMs. Conclusions CD11b might promote the development and progression of abdominal aortic aneurysm by mediating the endothelial cells adhesion and transendothelial migration of circulating monocytes/macrophages.
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Affiliation(s)
- Min Zhou
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
| | - Xia Wang
- Department of Ultrasound in Medicine Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai China
| | - Yiqin Shi
- Department of Nephrology Zhongshan Hospital Fudan University Shanghai China
| | - Yong Ding
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
| | - Xu Li
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
| | - Tianchen Xie
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
| | - Zhenyu Shi
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
| | - Weiguo Fu
- Department of Vascular Surgery Zhongshan Hospital Fudan University Shanghai China
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34
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Sim H, Jeong D, Kim HI, Pak S, Thapa B, Kwon HJ, Lee K. CD11b Deficiency Exacerbates Methicillin-Resistant Staphylococcus aureus-Induced Sepsis by Upregulating Inflammatory Responses of Macrophages. Immune Netw 2021; 21:e13. [PMID: 33996169 PMCID: PMC8099615 DOI: 10.4110/in.2021.21.e13] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/21/2020] [Accepted: 01/07/2021] [Indexed: 12/14/2022] Open
Abstract
Macrophages are important for the first line of defense against microbial pathogens. Integrin CD11b, which is encoded by Itgam, is expressed on the surface of macrophages and has been implicated in adhesion, migration, and cell-mediated cytotoxicity. However, the functional impact of CD11b on the inflammatory responses of macrophages upon microbial infection remains unclear. Here, we show that CD11b deficiency resulted in increased susceptibility to sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection by enhancing the pro-inflammatory activities of macrophages. Upon infection with MRSA, the mortality of Itgam knockout mice was significantly higher than that of control mice, which is associated with increased production of TNF-α and IL-6. In response to MRSA, both bone marrow-derived macrophages and peritoneal macrophages lacking CD11b produced elevated amounts of pro-inflammatory cytokines and nitric oxide. Moreover, CD11b deficiency upregulated IL-4-induced expression of anti-inflammatory mediators such as IL-10 and arginase-1, and an immunomodulatory function of macrophages to restrain T cell activation. Biochemical and confocal microscopy data revealed that CD11b deficiency augmented the activation of NF-κB signaling and phosphorylation of Akt, which promotes the functional activation of macrophages with pro-inflammatory and immunoregulatory phenotypes, respectively. Overall, our experimental evidence suggests that CD11b is a critical modulator of macrophages in response to microbial infection.
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Affiliation(s)
- Hyunsub Sim
- Department of Biomedical Science, College of Natural Science, Hallym University, Chuncheon 24252, Korea
| | - Daecheol Jeong
- Department of Biomedical Science, College of Natural Science, Hallym University, Chuncheon 24252, Korea
| | - Hye-In Kim
- Department of Biomedical Science, College of Natural Science, Hallym University, Chuncheon 24252, Korea
| | - Seongwon Pak
- Department of Biomedical Science, College of Natural Science, Hallym University, Chuncheon 24252, Korea
| | - Bikash Thapa
- Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea
| | - Hyung-Joo Kwon
- Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252, Korea
| | - Keunwook Lee
- Department of Biomedical Science, College of Natural Science, Hallym University, Chuncheon 24252, Korea.,Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea
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35
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Vandendriessche S, Cambier S, Proost P, Marques PE. Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front Cell Dev Biol 2021; 9:624025. [PMID: 33644062 PMCID: PMC7905230 DOI: 10.3389/fcell.2021.624025] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.
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Affiliation(s)
- Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Pedro E Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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Marques CPC, Rodrigues VP, de Carvalho LC, Nichilatti LP, Franco MM, Patrício FJB, Magalhães M, de Andrade MS, Benatti BB. Expression of Toll-like receptors 2 and 4 in the saliva of patients with systemic lupus erythematosus and chronic periodontitis. Clin Rheumatol 2021; 40:2727-2734. [PMID: 33570702 DOI: 10.1007/s10067-020-05560-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 11/08/2020] [Accepted: 12/21/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the expression of salivary Toll-like receptors (TRL) 2 and 4 in patients with systemic lupus erythematosus (SLE) and chronic periodontitis (CP). METHODS A case-control study was conducted with 77 participants (42 SLE and 35 non-SLE) stratified according to CP diagnosis criteria. Periodontal parameters consisted of clinical attachment level (CAL), probing depth (PD), the visible plaque index (VPI), and the gingival bleeding index (GBI). Salivary TRL 2 and 4 expressions were determined by quantitative real-time polymerase chain reaction (RT-PCR). Statistical analysis included Mann-Whitney U test, Kruskal-Wallis test, Spearman's correlation rank, and multiple linear regression. RESULTS Patients with isolated SLE or CP had higher TLR 2 and TLR 4 expression in their saliva samples (P < 0.05). The group with both SLE and CP had lower TLR 2 and 4 expressions (P < 0.05). TLR 2 and TLR 4 showed significant negative correlations with PD, CAL, and GBI in SLE patients, and a significant positive correlation with periodontal parameters in non-SLE patients. CP was independently associated with reduction of TLR2 and TLR4 expression, even after adjusting for clinical data and current drug use. CONCLUSION Reduced TRL 2 and 4 expression in saliva was associated with the presence of CP in SLE patients. Key Points • Patients affected by isolated CP or SLE had higher TLR2 and TLR4 expression. • TLR under-expression may be associated with a worse periodontal status in SLE. • Abnormalities in TLRs expression may increase the susceptibility to periodontitis.
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Affiliation(s)
- Consuelo P C Marques
- Dentistry Graduate Program, Federal University of Maranhão, São Luís, Maranhão, Brazil.,School of Medicine, Federal University of Maranhão, Pinheiro, Maranhão, Brazil
| | - Vandilson P Rodrigues
- Dentistry Graduate Program, Federal University of Maranhão, São Luís, Maranhão, Brazil. .,Research Group in Clinical and Molecular Endocrinology and Metabology (ENDOCLIM), President Dutra Hospital of the Federal University of Maranhão, São Luís, Maranhão, Brazil.
| | | | - Louise P Nichilatti
- School of Medicine, Federal University of Maranhão, Pinheiro, Maranhão, Brazil
| | - Mayra M Franco
- Dentistry Graduate Program, Federal University of Maranhão, São Luís, Maranhão, Brazil
| | - Fernando José B Patrício
- Laboratory of Genomic Studies and Histocompatibility, President Dutra Hospital of the Federal University of Maranhão, São Luís, Maranhão, Brazil
| | - Marcelo Magalhães
- Research Group in Clinical and Molecular Endocrinology and Metabology (ENDOCLIM), President Dutra Hospital of the Federal University of Maranhão, São Luís, Maranhão, Brazil
| | - Marcelo S de Andrade
- Laboratory of Genomic Studies and Histocompatibility, President Dutra Hospital of the Federal University of Maranhão, São Luís, Maranhão, Brazil
| | - Bruno B Benatti
- Dentistry Graduate Program, Federal University of Maranhão, São Luís, Maranhão, Brazil
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The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment. Cancers (Basel) 2021; 13:cancers13020210. [PMID: 33430105 PMCID: PMC7827203 DOI: 10.3390/cancers13020210] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 12/13/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Immunotherapy improved the therapeutic landscape for patients with advanced cancer diseases. However, many patients do not benefit from immunotherapy. The bidirectional crosstalk between myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) contributes to immune evasion, limiting the success of immunotherapy by checkpoint inhibitors. This review aims to outline the current knowledge of the role and the immunosuppressive properties of MDSC and Treg within the tumor microenvironment (TME). Furthermore, we will discuss the importance of the functional crosstalk between MDSC and Treg for immunosuppression, issuing particularly the role of cell adhesion molecules. Lastly, we will depict the impact of this interaction for cancer research and discuss several strategies aimed to target these pathways for tumor therapy. Abstract Immune checkpoint inhibitors (ICI) have led to profound and durable tumor regression in some patients with metastatic cancer diseases. However, many patients still do not derive benefit from immunotherapy. Here, the accumulation of immunosuppressive cell populations within the tumor microenvironment (TME), such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), contributes to the development of immune resistance. MDSC and Treg expand systematically in tumor patients and inhibit T cell activation and T effector cell function. Numerous studies have shown that the immunosuppressive mechanisms exerted by those inhibitory cell populations comprise soluble immunomodulatory mediators and receptor interactions. The latter are also required for the crosstalk of MDSC and Treg, raising questions about the relevance of cell–cell contacts for the establishment of their inhibitory properties. This review aims to outline the current knowledge on the crosstalk between these two cell populations, issuing particularly the potential role of cell adhesion molecules. In this regard, we further discuss the relevance of β2 integrins, which are essential for the differentiation and function of leukocytes as well as for MDSC–Treg interaction. Lastly, we aim to describe the impact of such bidirectional crosstalk for basic and applied cancer research and discuss how the targeting of these pathways might pave the way for future approaches in immunotherapy.
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Xu S, Ma Y, Chen Y, Pan F. Role of Forkhead box O3a transcription factor in autoimmune diseases. Int Immunopharmacol 2021; 92:107338. [PMID: 33412391 DOI: 10.1016/j.intimp.2020.107338] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/05/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Forkhead box O3a (FOXO3a) transcription factor, the most important member of Forkhead box O family, is closely related to cell proliferation, apoptosis, autophagy, oxidative stress and aging. The downregulation of FOXO3a has been verified to be associated with the poor prognosis, severer malignancy and chemoresistance in several human cancers. The activity of FOXO3a mainly regulated by phosphorylation of protein kinase B. FOXO3a plays a vital role in promoting the apoptosis of immune cells. FOXO3a could also modulate the activation, differentiation and function of T cells, regulate the proliferation and function of B cells, and mediate dendritic cells tolerance and immunity. FOXO3a accommodates the immune response through targeting nuclear factor kappa-B and FOXP3, as well as regulating the expression of cytokines. Besides, FOXO3a participates in intercellular interactions. FOXO3a inhibits dendritic cells from producing interleukin-6, which inhibits B-cell lymphoma-2 (BCL-2) and BCL-XL expression, thereby sparing resting T cells from apoptosis and increasing the survival of antigen-stimulated T cells. Recently, plentiful evidences further illustrated the significance of FOXO3a in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, myositis, multiple sclerosis, and systemic sclerosis. In this review, we focused on the biological function of FOXO3a and related signaling pathways regarding immune system, and summarized the potential role of FOXO3a in the pathogenesis, progress and therapeutic potential of autoimmune diseases.
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Affiliation(s)
- Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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Xiong ZH, Cao XS, Guan HL, Zheng HL. Immunotherapies application in active stage of systemic lupus erythematosus in pregnancy: A case report and review of literature. World J Clin Cases 2020; 8:6396-6407. [PMID: 33392323 PMCID: PMC7760451 DOI: 10.12998/wjcc.v8.i24.6396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/27/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Pregnancy in the setting of systemic lupus erythematosus can worsen the condition from the stable to active stage, with quality of life and fertility desire being particular concerns. Pregnancy in the active stage of systemic lupus erythematosus (ASLE), although rare and complicated to manage, can be treated favorably with immunotherapies ifs used properly. Here we report such a success case.
CASE SUMMARY A 31-year-old primigravida patient, diagnosed with SLE seven years ago, was induced ASLE after a cold at 21 + weeks. The patient’s vital signs on presentation were normal. Her laboratory exam was remarkable for significant proteinuria, liver and renal dysfunction, and low C3 and C4 levels. Infectious work-up was negative. The patient was diagnosed with ASLE. She was given immunosuppressive agents (methylprednisolone, gamma globulin and azathioprine etc.) and plasma adsorption therapy, monitoring blood pressure every 8 h, fetal heart rate twice a day, and liver and renal function at least twice a week. Successful maternal and fetal outcomes are presented here.
CONCLUSION Child-bearing in ASLE has become more promising, even for this difficult case of ASLE with multiple organ damage. Thorough antepartum counseling, cautious maternal-fetal monitoring, and multi-organ function monitoring by multidisciplinary specialties are keys to favorable pregnancy outcomes.
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Affiliation(s)
- Zhi-Hui Xiong
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Xiao-Song Cao
- Department of Medical Clinic, Lanxi No. 5 Middle School, Lanxi 321100, Zhejiang Province, China
| | - Hai-Lian Guan
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Hui-Ling Zheng
- Department of Obstetrics, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang Province, China
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40
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Ehirchiou D, Bernabei I, Chobaz V, Castelblanco M, Hügle T, So A, Zhang L, Busso N, Nasi S. CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis. Front Cell Dev Biol 2020; 8:611757. [PMID: 33392201 PMCID: PMC7775404 DOI: 10.3389/fcell.2020.611757] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/02/2020] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis (OA) is a progressive joint disease that is strongly associated with calcium-containing crystal formation (mineralization) by chondrocytes leading ultimately to cartilage calcification. However, this calcification process is poorly understood and treatments targeting the underlying disease mechanisms are lacking. The CD11b/CD18 integrin (Mac-1 or αMβ2), a member of the beta 2 integrin family of adhesion receptors, is critically involved in the development of several inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus. We found that in a collagen-induced arthritis, CD11b-deficient mice exhibited increased cartilage degradation compared to WT control animals. However, the functional significance of CD11b integrin signaling in the pathophysiology of chondrocytes remains unknown. CD11b expression was found in the extracellular matrix and in chondrocytes in both healthy and damaged human and murine articular cartilage. Primary murine CD11b KO chondrocytes showed increased mineralization when induced in vitro by secondary calciprotein particles (CPP) and quantified by Alizarin Red staining. This increased propensity to mineralize was associated with an increased alkaline phosphatase (Alp) expression (measured by qRT-PCR and activity assay) and an enhanced secretion of the pro-mineralizing IL-6 cytokine compared to control wild-type cells (measured by ELISA). Accordingly, addition of an anti-IL-6 receptor antibody to CD11b KO chondrocytes reduced significantly the calcification and identified IL-6 as a pro-mineralizing factor in these cells. In the same conditions, the ratio of qRT-PCR expression of collagen X over collagen II, and that of Runx2 over Sox9 (both ratio being indexes of chondrocyte hypertrophy) were increased in CD11b-deficient cells. Conversely, the CD11b activator LA1 reduced chondrocyte mineralization, Alp expression, IL-6 production and collagen X expression. In the meniscectomy (MNX) model of murine knee osteoarthritis, deficiency of CD11b led to more severe OA (OARSI scoring of medial cartilage damage in CD11b: 5.6 ± 1.8, in WT: 1.2 ± 0.5, p < 0.05, inflammation in CD11b: 2.8 ± 0.2, in WT: 1.4 ± 0.5). In conclusion, these data demonstrate that CD11b signaling prevents chondrocyte hypertrophy and chondrocyte mineralization in vitro and has a protective role in models of OA in vivo.
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Affiliation(s)
- Driss Ehirchiou
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Ilaria Bernabei
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Véronique Chobaz
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Mariela Castelblanco
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Thomas Hügle
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Alexander So
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Li Zhang
- Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Nathalie Busso
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Sonia Nasi
- Service of Rheumatology, Department of Musculoskeletal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Martinez L, Li X, Ramos-Echazabal G, Faridi H, Zigmond ZM, Santos Falcon N, Hernandez DR, Shehadeh SA, Velazquez OC, Gupta V, Vazquez-Padron RI. A Genetic Model of Constitutively Active Integrin CD11b/CD18. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:2545-2553. [PMID: 32938725 PMCID: PMC7577938 DOI: 10.4049/jimmunol.1901402] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 08/23/2020] [Indexed: 01/31/2023]
Abstract
Pharmacological activation of integrin CD11b/CD18 (αMβ2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes an active, higher-affinity conformation of the ligand-binding I/A-domain (CD11b αA-domain). In vitro, this mutation increased adhesion of knock-in neutrophils to fibrinogen and decreased neutrophil chemotaxis to a formyl-Met-Leu-Phe gradient. In vivo, CD11bI332G animals showed a reduction in recruitment of neutrophils and macrophages in a model of sterile peritonitis. This genetic activation of CD11b also protected against development of atherosclerosis in the setting of hyperlipidemia via reduction of macrophage recruitment into atherosclerotic lesions. Thus, our animal model of constitutive genetic activation of CD11b can be a useful tool for the study of integrin activation and its potential contribution to modulating leukocyte recruitment and alleviating different inflammatory diseases.
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Affiliation(s)
- Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Xiaobo Li
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612
| | - Gioser Ramos-Echazabal
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Hafeez Faridi
- Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University, Chicago, IL 60612; and
| | - Zachary M Zigmond
- Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Nieves Santos Falcon
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Diana R Hernandez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Serene A Shehadeh
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Omaida C Velazquez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Vineet Gupta
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612;
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136;
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Integrins Control Vesicular Trafficking; New Tricks for Old Dogs. Trends Biochem Sci 2020; 46:124-137. [PMID: 33020011 PMCID: PMC7531435 DOI: 10.1016/j.tibs.2020.09.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/24/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023]
Abstract
Integrins are transmembrane receptors that transduce biochemical and mechanical signals across the plasma membrane and promote cell adhesion and migration. In addition, integrin adhesion complexes are functionally and structurally linked to components of the intracellular trafficking machinery and accumulating data now reveal that they are key regulators of endocytosis and exocytosis in a variety of cell types. Here, we highlight recent insights into integrin control of intracellular trafficking in processes such as degranulation, mechanotransduction, cell–cell communication, antibody production, virus entry, Toll-like receptor signaling, autophagy, and phagocytosis, as well as the release and uptake of extracellular vesicles. We discuss the underlying molecular mechanisms and the implications for a range of pathophysiological contexts, including hemostasis, immunity, tissue repair, cancer, and viral infection.
Integrin adhesion complexes control polarized targeting of the intracellular trafficking machinery via microtubules. Integrin adhesions are exocytic hubs for a variety of vesicles, including lytic and dense granules, lysosome-related organelles, and biosynthetic vesicles. Integrin-dependent adhesion and signaling is required for degranulation of platelets and leukocytes and controls hemostasis and immunity. Specialized adhesion complexes containing integrin αvβ5 and clathrin are sites of frustrated endocytosis and hubs for mechanotransduction. Integrin control of endocytosis regulates Toll-like receptor signaling and autophagy in immune cells. Integrins control intercellular communication and viral transfer through extracellular vesicles.
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43
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Acharya M, Raso F, Sagadiev S, Gilbertson E, Kadavy L, Li QZ, Yan M, Stuart LM, Hamerman JA, Lacy-Hulbert A. B Cell αv Integrins Regulate TLR-Driven Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2020; 205:1810-1818. [PMID: 32859730 DOI: 10.4049/jimmunol.1901056] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 07/30/2020] [Indexed: 12/14/2022]
Abstract
Systemic lupus erythematosus (SLE) is defined by loss of B cell tolerance, resulting in production of autoantibodies against nucleic acids and other cellular Ags. Aberrant activation of TLRs by self-derived RNA and DNA is strongly associated with SLE in patients and in mouse models, but the mechanism by which TLR signaling to self-ligands is regulated remains poorly understood. In this study, we show that αv integrin plays a critical role in regulating B cell TLR signaling to self-antigens in mice. We show that deletion of αv from B cells accelerates autoantibody production and autoimmune kidney disease in the Tlr7.1 transgenic mouse model of SLE. Increased autoimmunity was associated with specific expansion of transitional B cells, extrafollicular IgG2c-producing plasma cells, and activation of CD4 and CD8 T cells. Our data show that αv-mediated regulation of TLR signaling in B cells is critical for preventing autoimmunity and indicate that loss of αv promotes escape from tolerance. Thus, we identify a new regulatory pathway in autoimmunity and elucidate upstream signals that adjust B cell activation to prevent development of autoimmunity in a mouse model.
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Affiliation(s)
- Mridu Acharya
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; .,Seattle Children's Research Institute, Seattle, WA 98101
| | - Fiona Raso
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101
| | - Sara Sagadiev
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.,Seattle Children's Research Institute, Seattle, WA 98101
| | - Emily Gilbertson
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101
| | - Lauren Kadavy
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101
| | - Quan Z Li
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Mei Yan
- Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Lynda M Stuart
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.,Bill and Melinda Gates Foundation, Seattle, WA 98109; and
| | - Jessica A Hamerman
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.,Department of Immunology, University of Washington, Seattle, WA 98109
| | - Adam Lacy-Hulbert
- Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; .,Department of Immunology, University of Washington, Seattle, WA 98109
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Bermejo-Jambrina M, Blatzer M, Jauregui-Onieva P, Yordanov TE, Hörtnagl P, Valovka T, Huber LA, Wilflingseder D, Posch W. CR4 Signaling Contributes to a DC-Driven Enhanced Immune Response Against Complement-Opsonized HIV-1. Front Immunol 2020; 11:2010. [PMID: 32922405 PMCID: PMC7457048 DOI: 10.3389/fimmu.2020.02010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/24/2020] [Indexed: 12/27/2022] Open
Abstract
Dendritic cells (DCs) possess intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. In turn, HIV-1 has evolved strategies to evade innate immune sensing by DCs resulting in suboptimal maturation and poor antiviral immune responses. We previously showed that complement-opsonized HIV-1 (HIV-C) was able to efficiently infect various DC subsets significantly higher than non-opsonized HIV-1 (HIV) and therefore also mediate a higher antiviral immunity. Thus, complement coating of HIV-1 might play a role with respect to viral control occurring early during infection via modulation of DCs. To determine in detail which complement receptors (CRs) expressed on DCs was responsible for infection and superior pro-inflammatory and antiviral effects, we generated stable deletion mutants for the α-chains of CR3, CD11b, and CR4, CD11c using CRISPR/Cas9 in THP1-derived DCs. We found that CD11c deletion resulted in impaired DC infection as well as antiviral and pro-inflammatory immunity upon exposure to complement-coated HIV-1. In contrast, sole expression of CD11b on DCs shifted the cells to an anti-inflammatory, regulatory DC type. We here illustrated that CR4 comprised of CD11c and CD18 is the major player with respect to DC infection associated with a potent early pro-inflammatory immune response. A more detailed characterization of CR3 and CR4 functions using our powerful tool might open novel avenues for early therapeutic intervention during HIV-1 infection.
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Affiliation(s)
- Marta Bermejo-Jambrina
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.,Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Michael Blatzer
- Experimental Neuropathology Unit, Infection and Epidemiology Department, Institute Pasteur, Paris, France
| | - Paula Jauregui-Onieva
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Teodor E Yordanov
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Paul Hörtnagl
- Central Institute for Blood Transfusion and Immunological Department, Innsbruck, Austria
| | - Taras Valovka
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.,Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas A Huber
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Doris Wilflingseder
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Wilfried Posch
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
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Xu W, Zhang Y, Wang X, Liu P, Gao D, Gu B, Zhang J, Li C, Ren Q, Yang L, Yuan H, Shen M, Chen X. Clinical features and expression of type I interferon-inducible genes in systemic lupus erythematosus patients harboring rs1143679 polymorphism in China: a single-center, retrospective study. Clin Rheumatol 2020; 40:1093-1101. [PMID: 32785810 DOI: 10.1007/s10067-020-05330-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 07/02/2020] [Accepted: 08/04/2020] [Indexed: 11/27/2022]
Abstract
OBJECTIVE This case-control study aimed to analyze the clinical features and determine the expression of type I interferon-induced genes in systemic lupus erythematosus (SLE) patients harboring the CD11b rs1143679 single-nucleotide polymorphism (SNP) and elucidate whether it is involved in the relapses of SLE. METHODS One hundred twenty-five relatively inactive SLE patients with SLEDAI scores < 6, including 102 CD11b rs1143679 G allele patients as controls and 23 rs1143679 A allele carriers as cases, were enrolled from the SLE patient specimen bank in the Department of Rheumatology and Immunology. The sample set was retrospectively analyzed for differences in clinical features, and quantitative PCR and Western blot analyses were performed to evaluate the relative expression of type I interferon (IFN)-inducible genes. RESULTS The 24-h urinary protein levels in the case group were significantly elevated, and serum C3 levels were significantly reduced compared with those in the control group (P = 0.019 and P = 0.021, respectively). The relative mRNA levels of IFN-inducible genes IFIT1, IFIT4, and ISG15 in the case group were higher than that in the control group (P = 0.0257, 0.0344, and 0.0311, respectively) and matched with the Western blot results. CONCLUSIONS The relative expression of type I IFN-inducible genes in inactive SLE patients harboring the CD11b rs1143679 polymorphism was higher than that in other lupus patients. These findings suggest that the rs1143679 SNP can precipitate relapses in inactive SLE patients. KEY POINTS • The rs1143679 GA genotype was associated with SLE clinical features. • The rs1143679 GA genotype showed higher interferon-inducible gene expression relative to the GG genotype.
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Affiliation(s)
- Wenyu Xu
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Yueyue Zhang
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Xiaoqin Wang
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Peiyu Liu
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China
| | - Dayu Gao
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Bingjie Gu
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Junyu Zhang
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Chunmei Li
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Qijie Ren
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Leilei Yang
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Hai Yuan
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Minning Shen
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China
| | - Xingguo Chen
- Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, China.
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Matta B, Barnes BJ. Coordination between innate immune cells, type I IFNs and IRF5 drives SLE pathogenesis. Cytokine 2020; 132:154731. [PMID: 31130331 PMCID: PMC11931518 DOI: 10.1016/j.cyto.2019.05.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 05/16/2019] [Accepted: 05/19/2019] [Indexed: 12/18/2022]
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease which affects multiple organs. The type I interferon (IFN) gene signature and circulating autoantibodies are hallmarks of SLE. Plasmacytoid dendritic cells (pDCs) are considered the main producers of type I IFN and production is modulated by multiple other immune cell types. In SLE, essentially every immune cell type is dysregulated and aberrant deregulation is thought to be due, in part, to direct or indirect exposure to IFN. Genetic variants within or around the transcription factor interferon regulatory factor 5 (IRF5) associate with SLE risk. Elevated IFNα activity was detected in the sera of SLE patients carrying IRF5 risk polymorphisms who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies. Neutrophils are also an important source of type I IFNs and are found in abundance in human blood. Neutrophil extracellular traps (NETs) are considered a potential source of antigenic trigger in SLE that can lead to type I IFN gene induction, as well as increased autoantibody production. In this review, we will focus on immune cell types that produce type I IFNs and/or are affected by type I IFN in SLE. In addition, we will discuss potential inducers of endogenous type I IFN production in SLE. Last, we will postulate how the different immune cell populations may be affected by an IRF5-SLE risk haplotype.
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Affiliation(s)
- Bharati Matta
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Betsy J Barnes
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA; Departments of Molecular Medicine and Pediatrics, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
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Hemmati S, Sadeghi MA, Yousefi-Manesh H, Eslamiyeh M, Vafaei A, Foroutani L, Donyadideh G, Dehpour A, Rezaei N. Protective Effects of Leukadherin1 in a Rat Model of Targeted Experimental Autoimmune Encephalomyelitis (EAE): Possible Role of P47phox and MDA Downregulation. J Inflamm Res 2020; 13:411-420. [PMID: 32821147 PMCID: PMC7423460 DOI: 10.2147/jir.s258991] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/22/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Reactive oxygen and nitrogen species (ROS and RNS) are involved in pathologic mechanisms underlying demyelination and exacerbation in multiple sclerosis (MS) lesions. P47phox is the most important subunit of an ROS-producing enzyme (NADPH oxidase) which is reportedly upregulated in MS plaques due to the intense activity of infiltrated immune cells and resident microglia. Leukadherin1 is a specific CD11b/CD18 agonist that inhibits signaling and transmigration of inflammatory cells to sites of injury. Based on this mechanism, we evaluated therapeutic effects of leukadherin1 in an animal model of targeted experimental autoimmune encephalomyelitis (EAE) through focal injection of inflammatory cytokines to the spinal cord. METHODS For model induction, Lewis rats were first immunized with 15µg MOG 1-125 emulsion. Twenty days later, animals were subjected to stereotaxic injection of IFNγ and TNFα to the specific spinal area (T8). One day after injection, all animals presented EAE clinical signs, and their behaviors were monitored for eight days through open-field locomotion and grid-walking tests. Leukadherin1-treated animals received daily intraperitoneal injections of 1mg/kg of the drug. The specific spinal tissues were extracted on day 5 in order to measure nitric oxide (NO), malon di-aldehyde (MDA), and TNFα concentrations alongside P47phox real-time PCR analysis. In addition, spinal sections were prepared for immunohistochemical (IHC) observation of infiltrated leukocytes and activated microglia. RESULTS Leukadherin1 exhibited promising improvements in EAE clinical scores and behavioral tests. Demyelination, CD45+ leukocyte infiltration, and Iba1+ microglia activation were reduced in spinal tissues of leukadherin1-treated animals. Furthermore, P47phox expression levels, MDA, and NO amounts were decreased in treated animals. However, TNFα concentrations did not differ following treatment. CONCLUSION Based on our results, we suggest that leukadherin1 may be used as a novel therapeutic agent in tackling the clinical challenge of multiple sclerosis, especially during the acute phase of the disease. This effect was possibly mediated through decreased leukocyte infiltration and oxidative stress.
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Affiliation(s)
- Sara Hemmati
- Molecular Medicine Interest Group (MMIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Sadeghi
- Molecular Medicine Interest Group (MMIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hasan Yousefi-Manesh
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Vafaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Laleh Foroutani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - AhmadReza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Panni RZ, Herndon JM, Zuo C, Hegde S, Hogg GD, Knolhoff BL, Breden MA, Li X, Krisnawan VE, Khan SQ, Schwarz JK, Rogers BE, Fields RC, Hawkins WG, Gupta V, DeNardo DG. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2020; 11:11/499/eaau9240. [PMID: 31270275 DOI: 10.1126/scitranslmed.aau9240] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 05/20/2019] [Indexed: 12/12/2022]
Abstract
Although checkpoint immunotherapies have revolutionized the treatment of cancer, not all tumor types have seen substantial benefit. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which very limited responses to immunotherapy have been observed. Extensive immunosuppressive myeloid cell infiltration in PDAC tissues has been postulated as a major mechanism of resistance to immunotherapy. Strategies concomitantly targeting monocyte or granulocyte trafficking or macrophage survival, in combination with checkpoint immunotherapies, have shown promise in preclinical studies, and these studies have transitioned into ongoing clinical trials for the treatment of pancreatic and other cancer types. However, compensatory actions by untargeted monocytes, granulocytes, and/or tissue resident macrophages may limit the therapeutic efficacy of such strategies. CD11b/CD18 is an integrin molecule that is highly expressed on the cell surface of these myeloid cell subsets and plays an important role in their trafficking and cellular functions in inflamed tissues. Here, we demonstrate that the partial activation of CD11b by a small-molecule agonist (ADH-503) leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models. These data demonstrate that molecular agonism of CD11b reprograms immunosuppressive myeloid cell responses and potentially bypasses the limitations of current clinical strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Roheena Z Panni
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - John M Herndon
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chong Zuo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samarth Hegde
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Graham D Hogg
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Brett L Knolhoff
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Marcus A Breden
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Xiaobo Li
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Varintra E Krisnawan
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samia Q Khan
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - Julie K Schwarz
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.,Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Buck E Rogers
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.,Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - William G Hawkins
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Vineet Gupta
- Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| | - David G DeNardo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. .,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Kahlenberg JM. Rethinking the Pathogenesis of Cutaneous Lupus. J Invest Dermatol 2020; 141:32-35. [PMID: 32605817 DOI: 10.1016/j.jid.2020.05.077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/29/2020] [Accepted: 05/01/2020] [Indexed: 10/24/2022]
Abstract
Knowledge of the etiology of cutaneous lupus is rapidly evolving. Dissection of the pathologic events in lesional skin has led to knowledge of important cell populations and transcriptional changes contributing to disease. Recently, the study of nonlesional skin in patients with systemic lupus has also identified key abnormalities that likely contribute to a propensity for inflammation. These include an elevated type I IFN signature, overproduction of IFNs, and an absence of Langerhans cells. These changes promote aberrant inflammation in response to known triggers of disease, such as UV light. Further research will undoubtedly accelerate our understanding of this disfiguring disease.
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Affiliation(s)
- J Michelle Kahlenberg
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
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50
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Zhao Q, Lu L, Du G, Wang Z, Li X, Ju F. 15-hydroxy-6 α,12-epoxy-7 β,10 αH,11 βH-spiroax-4-ene-12-one sensitizes rectal tumor cells to anti-PD1 treatment through agonism of CD11b. Immunopharmacol Immunotoxicol 2020; 42:358-365. [PMID: 32508184 DOI: 10.1080/08923973.2020.1778722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE Although immunotherapies have resulted in durable clinical responses, not all tumor types have seen substantial benefit. Extensive recruitment and accumulation of immunosuppressive myeloid cells into the tumor tissues has been postulated as a major mechanism of resistance to immunotherapies. Strategies targeting on single immunosuppressive cell type, in combination with checkpoint inhibitors, have resulted in promising outcomes in animal studies. However, compensatory actions by untargeted cells may limit the therapeutic efficacy. CD11b is highly expressed on the myeloid cell surface with an important role in their trafficking and cellular functions.In this study, we demonstrated that activation of CD11b with 15-hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO) enhanced the therapeutic efficacy of anti-PD1 treatment in the tumor model. MATERIALS AND METHODS A syngeneic rectal tumor model was established. Different types of cells from the peripheral blood and tumor tissues were analyzed by flow cytometry. Real-time PCR was used to detect the gene expression. Therapeutic effects of HESEO combining with anti-PD1 antibody were assessed by the tumor model. RESULTS Our data demonstrated that HESEO repolarized tumor-associated macrophages and reduced the number of tumor-infiltrating immunosuppressive myeloid cells. We further demonstrated that HESEO and immunotherapy combination promoted tumor growth control in a syngeneic tumor model. CONCLUSIONS Our results showed that HESEO improved anti-tumor T cell immunity and rendered anti-PD1 treatment effective in unresponsive tumor models, providing proof of concept for a new combination strategy involving molecular agonism of CD11b to bypass the limitations of current clinical strategies to overcome resistance to immunotherapies.
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Affiliation(s)
- Qingye Zhao
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
| | - Lin Lu
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
| | - Guowei Du
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
| | - Zhihai Wang
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
| | - Xutong Li
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
| | - Fang Ju
- Department of Oncology, The Center Hospital of Qingdao, Qingdao, P.R. China
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