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Liu S, Wang M, Xu L, Deng D, Lu L, Tian J, Zhou D, Rui K. New insight into the role of SOCS family in immune regulation and autoimmune pathogenesis. J Adv Res 2025:S2090-1232(25)00313-3. [PMID: 40349956 DOI: 10.1016/j.jare.2025.05.020] [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: 11/20/2024] [Revised: 04/07/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Suppressor of cytokine signaling (SOCS) proteins regulate signal transduction by interacting with cytokine receptors and signaling proteins and targeting associated proteins for degradation. Recent studies have demonstrated that the SOCS proteins serve as crucial inhibitors in cytokine signaling networks and play a pivotal role in both innate and adaptive immune responses. AIM OF REVIEW In this review, we aim to discuss recent advancements in understanding the complex functions of SOCS proteins in various immune cells, as well as the effects of SOCS proteins in human health and diseases. Increasing evidence indicates that SOCS proteins are frequently dysregulated in developing autoimmune diseases, suggesting that therapeutic targeting of SOCS proteins could provide clinical benefit. KEY SCIENTIFIC CONCEPTS OF REVIEW This review provides a comprehensive understanding of SOCS proteins in immune regulation and autoimmune pathogenesis, it also highlights the role of SOCS-related mimetic peptides in immunotherapy.
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Affiliation(s)
- Shiyi Liu
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Mingwei Wang
- Department of Emergency, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Liangjie Xu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Daihua Deng
- Department of Rheumatology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Chongqing International Institute for Immunology, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Dongmei Zhou
- Department of Rheumatology and Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Salauddin M, Bhattacharyya D, Samanta I, Saha S, Xue M, Hossain MG, Zheng C. Role of TLRs as signaling cascades to combat infectious diseases: a review. Cell Mol Life Sci 2025; 82:122. [PMID: 40105962 PMCID: PMC11923325 DOI: 10.1007/s00018-025-05631-x] [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: 06/05/2024] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
Investigating innate immunity and its signaling transduction is essential to understand inflammation and host defence mechanisms. Toll-like receptors (TLRs), an evolutionarily ancient group of pattern recognition receptors, are crucial for detecting microbial components and initiating immune responses. This review summarizes the mechanisms and outcomes of TLR-mediated signaling, focusing on motifs shared with other immunological pathways, which enhances our understanding of the innate immune system. TLRs recognize molecular patterns in microbial invaders, activate innate immunity and promote antigen-specific adaptive immunity, and each of them triggers unique downstream signaling patterns. Recent advances have highlighted the importance of supramolecular organizing centers (SMOCs) in TLR signaling, ensuring precise cellular responses and pathogen detection. Furthermore, this review illuminates how TLR pathways coordinate metabolism and gene regulation, contributing to adaptive immunity and providing novel insights for next-generation therapeutic strategies. Ongoing studies hold promise for novel treatments against infectious diseases, autoimmune conditions, and cancers.
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Affiliation(s)
- Md Salauddin
- Department of Microbiology and Public Health, Faculty of Veterinary, Animal and Biomedical Sciences, Khulna Agricultural University, Khulna, 9202, Bangladesh
| | - Debaraj Bhattacharyya
- Department of Veterinary Biochemistry, West Bengal University of Animal and Fishery Sciences, 37, K.B. Sarani, Kolkata, West Bengal, 700037, India
| | - Indranil Samanta
- Department of Veterinary Microbiology, West Bengal University of Animal and Fishery Sciences, 37, K.B. Sarani, Kolkata, West Bengal, 700037, India
| | - Sukumar Saha
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Mengzhou Xue
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, 2 Jingba Road, Zhengzhou, 450001, Henan, China.
| | - Md Golzar Hossain
- Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh.
| | - Chunfu Zheng
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
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3
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Wang AG, Son M, Gorin A, Kenna E, Padhi A, Keisham B, Schauer A, Hoffmann A, Tay S. Macrophage memory emerges from coordinated transcription factor and chromatin dynamics. Cell Syst 2025; 16:101171. [PMID: 39938520 PMCID: PMC12147866 DOI: 10.1016/j.cels.2025.101171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 09/18/2024] [Accepted: 01/09/2025] [Indexed: 02/14/2025]
Abstract
Cells of the immune system operate in dynamic microenvironments where the timing, concentration, and order of signaling molecules constantly change. Despite this complexity, immune cells manage to communicate accurately and control inflammation and infection. It is unclear how these dynamic signals are encoded and decoded and if individual cells retain the memory of past exposure to inflammatory molecules. Here, we use live-cell analysis, ATAC sequencing, and an in vivo model of sepsis to show that sequential inflammatory signals induce memory in individual macrophages through reprogramming the nuclear factor κB (NF-κB) network and the chromatin accessibility landscape. We use transcriptomic profiling and deep learning to show that transcription factor and chromatin dynamics coordinate fine-tuned macrophage responses to new inflammatory signals. This work demonstrates how macrophages retain the memory of previous signals despite single-cell variability and elucidates the mechanisms of signal-induced memory in dynamic inflammatory conditions like sepsis.
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Affiliation(s)
- Andrew G Wang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA
| | - Minjun Son
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA; Chan Zuckerberg Biohub Chicago, Chicago, IL, USA
| | - Aleksandr Gorin
- Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Emma Kenna
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Abinash Padhi
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Bijentimala Keisham
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Adam Schauer
- Chan Zuckerberg Biohub Chicago, Chicago, IL, USA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Savaş Tay
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
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Hou FF, Mi JH, Wang Q, Tao YL, Guo SB, Ran GH, Wang JC. Macrophage polarization in sepsis: Emerging role and clinical application prospect. Int Immunopharmacol 2025; 144:113715. [PMID: 39626538 DOI: 10.1016/j.intimp.2024.113715] [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: 10/21/2024] [Revised: 11/22/2024] [Accepted: 11/24/2024] [Indexed: 12/15/2024]
Abstract
Sepsis is a severe, potentially fatal condition defined by organ dysfunction due to excessive inflammation. Its complex pathogenesis and poor therapeutic outcomes pose significant challenges in treatment. Macrophages, with their high heterogeneity and plasticity, play crucial roles in both the innate and adaptive immune systems. They can polarize into M1-like macrophages, which promote pro-inflammatory responses, or M2-like macrophages, which mediate anti-inflammatory responses, positioning them as critical mediators in the immune response during sepsis.Macrophages are the main regulators of inflammatory responses, and their polarization is also regulated by inflammatory signaling pathways. This review highlights recent advances in the inflammatory signaling pathways involved in sepsis, mechanism of macrophage polarization mediated by inflammation-related signaling pathways in sepsis, and the role of signaling pathway mediated macrophage polarization in organ dysfunction involved in sepsis. We also explore the therapeutic potential of targeting macrophage polarization for immunotherapy, offering new perspectives on macrophage-targeted treatments for sepsis.
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Affiliation(s)
- Fei Fei Hou
- Intensive Care Unit Inner Mongolia Medical University Affiliated Hospital, Hohhot 010050, China
| | - Jun Hao Mi
- Liuzhou Maternity and Child Healthcare Hospital, Liuzhou 545001, China
| | - Qiong Wang
- Burn and Plastic Surgery Department of Hohhot First Hospital, Hohhot 010030, China
| | - Yan Lin Tao
- Intensive Care Unit Inner Mongolia Medical University Affiliated Hospital, Hohhot 010050, China
| | - Shuai Bin Guo
- Intensive Care Unit Inner Mongolia Medical University Affiliated Hospital, Hohhot 010050, China
| | - Guang He Ran
- Chongqing Changshou Traditional Cinese Medicine Hospital, 401200 Chongqing, China.
| | - Jing Chao Wang
- Intensive Care Unit Inner Mongolia Medical University Affiliated Hospital, Hohhot 010050, China.
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Li F, Wang T, Lin P, Wang Y, Chen Y, Feng J. SOCS6, an inhibitory factor in Japanese eel inhibits the type I IFN pathway and the MyD88-mediated NF-kB pathway. FISH & SHELLFISH IMMUNOLOGY 2024; 154:109901. [PMID: 39276815 DOI: 10.1016/j.fsi.2024.109901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
SOCS family genes are a class of repressors in various signaling pathways of mammals involved in regulating immunity, growth, and development, but the information remains limited in teleost. The full-length cDNA sequence of the Japanese eel SOCS6 gene, named AjSOCS6, was first cloned and showed to encode 529 amino acids with a conserved SH2 structural domain and a typical structure of a C-terminal SOCS box. AjSOCS6 is evolutionarily close to that of rainbow trout and zebrafish. AjSOCS6 gene expression was observed across all tissues in Japanese eel, with the highest levels found in the intestine. In vivo studies showed that AjSOCS6 was significantly upregulated in the liver following exposure to LPS, poly I:C, and Aeromonas hydrophila infection. In vitro, stimulation with poly I:C, CpG, and A. hydrophila infection increased AjSOCS6 expression in Japanese eel liver cells. Subcellular localization revealed that AjSOCS6 was dispersed in the cytoplasm. Overexpressing AjSOCS6 significantly suppressed the expression of immune-related genes, such as c-Rel and p65 in the NF-κB pathway, IFN1, IFN2, and IFN4 in the type I IFN signaling pathway, and the downstream inflammatory factor IL-6 in Japanese eel liver cells. Conversely, knocking down AjSOCS6 in vitro in liver cells and in vivo in the liver, spleen, and kidney significantly upregulated these gene expressions. Co-transfection of AjSOCS6 with AjMyD88 into HEK293 cells significantly reduced NF-κB luciferase activities compared to AjMyD88 single-transfection groups, in a natural state and under LPS stimulation. These findings suggest that AjSOCS6 negatively regulates MyD88-dependent NF-κB and type I IFN signaling pathways, underscoring its role in the immune defense of fish against viral and bacterial infections.
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Affiliation(s)
- Fuyan Li
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Tianyu Wang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Peng Lin
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Yilei Wang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Yun Chen
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Jianjun Feng
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, China; Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China.
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Li Y, Yang J, Wang X, Luoreng Z. Transcriptome analysis reveals the regulation of miR-19b on inflammation in bovine mammary epithelial cells. Microb Pathog 2024; 197:107082. [PMID: 39461446 DOI: 10.1016/j.micpath.2024.107082] [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: 05/21/2024] [Revised: 10/10/2024] [Accepted: 10/23/2024] [Indexed: 10/29/2024]
Abstract
MicroRNAs (miRNAs) are involved in various biological processes where they regulate the expression of mRNAs. Bovine mammary epithelial cells (bMECs) are functional cells that mediate mammary inflammatory immunity. Although numerous miRNAs regulate the function of bMECs, the role of miR-19b in bMECs has not been reported. In this study, the transcriptome of miR-19b overexpressed bMECs was analyzed by RNA-seq. Additionally, the differentially expressed genes (DEGs) were analyzed to establish the role of miR-19b in bMECs. The results revealed 269 DEGs between the miR-19b overexpression group and the negative control, including 199 up-regulated and 70 down-regulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the DEGs regulated immune and inflammatory responses through Staphylococcus aureus (S. aureus) infection and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In addition, the expression of miR-19b was significantly upregulated in lipophosphoric acid (LTA)-induced bMECs, and overexpression of miR-19b negatively regulated the expression of inflammatory cytokines IL-1β and IL-6, thereby alleviating the inflammatory response of LTA-induced bMECs. Based on the above results, we speculate that miR-19b may inhibit in dairy cow mammary inflammation caused by S. aureus, and this process may be mediated through the regulation of relevant gene expression and signaling pathways. The findings from this study provide a new reference for analyzing the molecular regulation of miR-19b in bMECs.
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Affiliation(s)
- Yuhang Li
- College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Jian Yang
- College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China
| | - Xingping Wang
- College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China.
| | - Zhuoma Luoreng
- College of Animal Science and Technology, Ningxia University, Yinchuan 750021, China; Key Laboratory of Ruminant Molecular Cell Breeding, Ningxia Hui Autonomous Region, Yinchuan 750021, China.
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Fathima A, Jamma T. UDCA ameliorates inflammation driven EMT by inducing TGR5 dependent SOCS1 expression in mouse macrophages. Sci Rep 2024; 14:24285. [PMID: 39414916 PMCID: PMC11484976 DOI: 10.1038/s41598-024-75516-9] [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: 05/29/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024] Open
Abstract
Long-standing chronic inflammation of the digestive tract leads to Inflammatory Bowel Diseases (IBD), comprising Crohn's Disease (CD) and Ulcerative colitis (UC). The persistent prevalence of these conditions in the gut is a predisposing factor for Colitis-Associated Cancer (CAC), one of the most common sub-types of Colorectal Cancer (CRC), emphasizing the role of inflammation in tumorigenesis. Therefore, targeted intervention of chronic intestinal inflammation is a potential strategy for preclusion and treatment of inflammation-driven malignancies. The association between bile acids (BA) and gut immune homeostasis has been explored in the recent past. However, the exact downstream mechanism by which secondary BA successfully regulating intestinal inflammation and inflammation-dependent CAC is unclear. Our study demonstrated that Ursodeoxycholic acid (UDCA), a secondary bile acid of host gut microbial origin, finetunes the dialogue between activated macrophages and intestinal epithelial cells, modulating inflammation-driven epithelial-mesenchymal transition (EMT), a hallmark of cancer. UDCA treatment and dependency on the TGR5/GPBAR1 receptor significantly upregulated the Suppressor of Cytokine Signaling 1 (SOCS1) expression, contributing to the regulation of pro-inflammatory cytokines in activated macrophages. In this study, we also noticed heightened expression of SOCS1 in UDCA-mitigated CAC in the AOM-DSS mouse model with reduced inflammatory gene expression. Overall, our observations highlight the possible utility of UDCA for inflammation-driven intestinal cancer.
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Affiliation(s)
- Ashna Fathima
- Cell Signaling Laboratory, Department of Biological Sciences, Birla Institute of Technology, and Science-Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, Telangana , India
| | - Trinath Jamma
- Cell Signaling Laboratory, Department of Biological Sciences, Birla Institute of Technology, and Science-Pilani Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, Telangana , India.
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8
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Sun L, Yang K, Wang L, Wu S, Wen D, Wang J. LncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by promoting autophagy through miR-30a-5p/SOCS1 axi. Sci Rep 2024; 14:22608. [PMID: 39349964 PMCID: PMC11442610 DOI: 10.1038/s41598-024-73607-1] [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: 06/12/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Accumulated data implicate that long noncoding RNA (lncRNA) plays a pivotal role in rheumatoid arthritis (RA), potentially serving as a competitive endogenous RNA (ceRNA) for microRNAs (miRNAs). The lncRNA myocardial infarction-associated transcript (MIAT) has been demonstrated to regulate inflammation. However, the role of MIAT in the inflammation of RA remains inadequately explored. This study aims to elucidate MIAT's role in the inflammation of lipopolysaccharide (LPS)-induced macrophages and to uncover the underlying molecular mechanisms. We observed heightened MIAT expression in LPS-induced J774A.1 cells and collagen-induced arthritis mouse models, in contrast to the expression pattern of miR-30a-5p. Silencing MIAT resulted in increased expression of the inflammatory cytokines IL-1β and TNF-α. Simultaneously, MIAT interference significantly impeded macrophage autophagy, evidenced by decreased expression of autophagy-related markers LC3-II and Beclin-1, alongside increased levels of p62 in LPS-induced J774A.1 cells. Notably, MIAT functioned as a ceRNA, sponging miR-30a-5p and exerting a negative regulatory influence on its expression. SOCS1 emerged as a target of miR-30a-5p, modulated by MIAT. Mechanistically, inhibiting miR-30a-5p reversed the impact of MIAT deficiency in promoting LPS-induced inflammation, while SOCS1 knockdown countered the cytokine inhibitory effect induced by silencing miR-30a-5p. In summary, this study indicates that lncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by stimulating autophagy through the miR-30a-5p/SOCS1 axis. This suggests that MIAT holds promise as a potential therapeutic target for RA inflammation.
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Affiliation(s)
- Linqian Sun
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Kun Yang
- Medical Research Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liqin Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Si Wu
- Department of Infectious Disease, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Dawei Wen
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jibo Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Zhang S, Yu B, Sheng C, Yao C, Liu Y, Wang J, Zeng Q, Mao Y, Bei J, Zhu B, Chen S. SHISA3 Reprograms Tumor-Associated Macrophages Toward an Antitumoral Phenotype and Enhances Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403019. [PMID: 39054639 PMCID: PMC11423144 DOI: 10.1002/advs.202403019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/22/2024] [Indexed: 07/27/2024]
Abstract
The main challenge for immune checkpoint blockade (ICB) therapy lies in immunosuppressive tumor microenvironment (TME). Repolarizing M2-like tumor-associated macrophages (TAMs) into inflammatory M1 phenotype is a promising strategy for cancer immunotherapy. Here, this study shows that the tumor suppressive protein SHISA3 regulates the antitumor functions of TAMs. Local delivery of mRNA encoding Shisa3 enables cancer immunotherapy by reprogramming TAMs toward an antitumoral phenotype, thus enhancing the efficacy of programmed cell death 1 (PD-1) antibody. Enforced expression of Shisa3 in TAMs increases their phagocytosis and antigen presentation abilities and promotes CD8+ T cell-mediated antitumor immunity. The expression of SHISA3 is induced by damage/pathogen-associated molecular patterns (DAMPs/PAMPs) in macrophages via nuclear factor-κB (NF-κB) transcription factors. Reciprocally, SHISA3 forms a complex with heat shock protein family A member 8 (HSPA8) to activate NF-κB signaling thus maintaining M1 polarization of macrophages. Knockout Shisa3 largely abolishes the antitumor efficacy of combination immunotherapy with Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and PD-1 antibody. It further found that higher expression of SHISA3 in antitumoral TAMs is associated with better overall survival in lung cancer patients. Taken together, the findings describe the role of SHISA3 in reprogramming TAMs that ameliorate cancer immunotherapy.
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Affiliation(s)
- Shimeng Zhang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Bingbing Yu
- Key Laboratory of Molecular Biophysicsthe Ministry of EducationCollege of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanHubei430074P. R. China
| | - Chunjie Sheng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Chen Yao
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Yang Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Jing Wang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Qi Zeng
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Yizhi Mao
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Jinxin Bei
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Bin Zhu
- Key Laboratory of Molecular Biophysicsthe Ministry of EducationCollege of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanHubei430074P. R. China
- Shenzhen Huazhong University of Science and Technology Research InstituteShenzhen518063P. R. China
| | - Shuai Chen
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
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Rane SS, Shellard E, Adamson A, Eyre S, Warren RB. IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease. Exp Dermatol 2024; 33:e15180. [PMID: 39306854 DOI: 10.1111/exd.15180] [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: 05/03/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024]
Abstract
Psoriasis is an incurable immune-mediated skin disease, affecting around 1%-3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.
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Affiliation(s)
- Shraddha S Rane
- Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Elan Shellard
- Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Antony Adamson
- Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Steve Eyre
- Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Richard B Warren
- Manchester Academic Health Science Centre, Faculty of Biology Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Dermatology Centre, Northern Care Alliance NHS Foundation Trust, Manchester, UK
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11
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Sawoo R, Bishayi B. TLR4/TNFR1 blockade suppresses STAT1/STAT3 expression and increases SOCS3 expression in modulation of LPS-induced macrophage responses. Immunobiology 2024; 229:152840. [PMID: 39126792 DOI: 10.1016/j.imbio.2024.152840] [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: 12/15/2023] [Revised: 07/15/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024]
Abstract
Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis.
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Affiliation(s)
- Ritasha Sawoo
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Biswadev Bishayi
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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12
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Qassim HA, Mohammed ST, Muhamed HJ. The impact of miRNA-155 in acute and chronic toxoplasmosis in Iraqi women. Acta Trop 2024; 255:107211. [PMID: 38678844 DOI: 10.1016/j.actatropica.2024.107211] [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: 12/20/2023] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/01/2024]
Abstract
Toxoplasmosis is a prevalent parasitic infection caused by Toxoplasma gondii known to induce complex immune responses, to control the infection. MicroRNAs (miRNAs) are a cluster of small noncoding RNAs that are reported to have regulatory functions in the immune response. The objective of this study is to assess the expression of miR-155 and its targets, Src homology-2 domain-containing inositol 5- phosphatase 1 (SHIP-1) and suppressor of cytokine signaling-1 (SOCS1), in non-pregnant Iraqi women seropositive for toxoplasmosis. The study included 55 non-pregnant women positive for toxoplasmosis (20 in the acute phase and 35 in the chronic phase) and 35 non-pregnant women negative for toxoplasmosis (control group). Serum samples were collected from all participants to investigate the expression of miR-155 by RT‒PCR, in addition to the levels of SOCS1 and SHIP-1 measured by ELISA. The results showed a significant increase in the expression of miR-155 in both groups of acute and chronic toxoplasmosis compared to the control group. Lower levels of SOCS1 and SHIP-1 were found in acutely infected women compared to those with chronic infection and non-infected women. These findings showed the possible critical impact of miR-155 on host immune response during T.gondii infection, proposing that miR-155 can be explored as a prospective target to support host immune response against infectious diseases, with special help in early detection and management of toxoplasmosis in high-risk immunocompromised patients. Further studies are needed to evaluate the molecular pathways by which miRNAs improve immunity against toxoplasmosis.
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Affiliation(s)
- Hiba A Qassim
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq.
| | - Sabaa T Mohammed
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq
| | - Haider J Muhamed
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq
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13
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Wang T, Ge H, Lin P, Wang Y, Lai X, Chen P, Li F, Feng J. Toll-interacting protein is activated by the transcription factor GATA1 and Sp1 to negatively regulate NF-κB and MAPK pathways in the Japanese eel (Anguilla japonica). FISH & SHELLFISH IMMUNOLOGY 2024; 149:109561. [PMID: 38636738 DOI: 10.1016/j.fsi.2024.109561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 04/11/2024] [Accepted: 04/11/2024] [Indexed: 04/20/2024]
Abstract
Toll-interacting protein (Tollip) serves as a crucial inhibitory factor in the modulation of Toll-like receptor (TLR)-mediated innate immunological responses. The structure and function of Tollip have been well documented in mammals, yet the information in teleost remained limited. This work employed in vitro overexpression and RNA interference in vivo and in vitro to comprehensively examine the regulatory effects of AjTollip on NF-κB and MAPK signaling pathways. The levels of p65, c-Fos, c-Jun, IL-1, IL-6, and TNF-α were dramatically reduced following overexpression of AjTollip, whereas knocking down AjTollip in vivo and in vitro enhanced those genes' expression. Protein molecular docking simulations showed AjTollip interacts with AjTLR2, AjIRAK4a, and AjIRAK4b. A better understanding of the transcriptional regulation of AjTollip is crucial to elucidating the role of Tollip in fish antibacterial response. Herein, we cloned and characterized a 2.2 kb AjTollip gene promoter sequence. The transcription factors GATA1 and Sp1 were determined to be associated with the activation of AjTollip expression by using promoter truncation and targeted mutagenesis techniques. Collectively, our results indicate that AjTollip suppresses the NF-κB and MAPK signaling pathways, leading to the decreased expression of the downstream inflammatory factors, and GATA1 and Sp1 play a vital role in regulating AjTollip expression.
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Affiliation(s)
- Tianyu Wang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Hui Ge
- Key Laboratory of Cultivation and High-value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen, 361012, China
| | - Peng Lin
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Yilei Wang
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Xiaojian Lai
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Pengyun Chen
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Fuyan Li
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China
| | - Jianjun Feng
- Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China; Key Laboratory of Cultivation and High-value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen, 361012, China; Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Fisheries College, Jimei University, Xiamen, Fujian Province, 361021, China.
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14
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Ma Y, Jiang T, Zhu X, Xu Y, Wan K, Zhang T, Xie M. Efferocytosis in dendritic cells: an overlooked immunoregulatory process. Front Immunol 2024; 15:1415573. [PMID: 38835772 PMCID: PMC11148234 DOI: 10.3389/fimmu.2024.1415573] [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: 04/10/2024] [Accepted: 05/09/2024] [Indexed: 06/06/2024] Open
Abstract
Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
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Affiliation(s)
- Yanyan Ma
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Tangxing Jiang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Xun Zhu
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yizhou Xu
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ke Wan
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Tingxuan Zhang
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Miaorong Xie
- Department of Emergency and Critical Care Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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15
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López-Collazo E, del Fresno C. Endotoxin tolerance and trained immunity: breaking down immunological memory barriers. Front Immunol 2024; 15:1393283. [PMID: 38742111 PMCID: PMC11089161 DOI: 10.3389/fimmu.2024.1393283] [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: 02/28/2024] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
For decades, innate immune cells were considered unsophisticated first responders, lacking the adaptive memory of their T and B cell counterparts. However, mounting evidence demonstrates the surprising complexity of innate immunity. Beyond quickly deploying specialized cells and initiating inflammation, two fascinating phenomena - endotoxin tolerance (ET) and trained immunity (TI) - have emerged. ET, characterized by reduced inflammatory response upon repeated exposure, protects against excessive inflammation. Conversely, TI leads to an enhanced response after initial priming, allowing the innate system to mount stronger defences against subsequent challenges. Although seemingly distinct, these phenomena may share underlying mechanisms and functional implications, blurring the lines between them. This review will delve into ET and TI, dissecting their similarities, differences, and the remaining questions that warrant further investigation.
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Affiliation(s)
- Eduardo López-Collazo
- The Innate Immune Response Group, Hospital la Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER), Respiratory Diseases (CIBRES), Madrid, Spain
| | - Carlos del Fresno
- The Innate Immune Response Group, Hospital la Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
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16
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Carpenter S, O'Neill LAJ. From periphery to center stage: 50 years of advancements in innate immunity. Cell 2024; 187:2030-2051. [PMID: 38670064 PMCID: PMC11060700 DOI: 10.1016/j.cell.2024.03.036] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/24/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50th anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.
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Affiliation(s)
- Susan Carpenter
- University of California Santa Cruz, 1156 High St., Santa Cruz, CA 95064, USA.
| | - Luke A J O'Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
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17
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Lyu J, Sheng M, Cao Y, Jia L, Zhang C, Weng Y, Yu W. Ischemia and reperfusion-injured liver-derived exosomes elicit acute lung injury through miR-122-5p regulated alveolar macrophage polarization. Int Immunopharmacol 2024; 131:111853. [PMID: 38503014 DOI: 10.1016/j.intimp.2024.111853] [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: 11/02/2023] [Revised: 02/16/2024] [Accepted: 03/10/2024] [Indexed: 03/21/2024]
Abstract
Acute lung injury (ALI) is a common postoperative complication, particularly in pediatric patients after liver transplantation. Hepatic ischemia-reperfusion (HIR) increases the release of exosomes (IR-Exos) in peripheral circulation. However, the role of IR-Exos in the pathogenesis of ALI induced by HIR remains unclear. Here, we explored the role of exosomes derived from the HIR-injured liver in ALI development. Intravenous injection of IR-Exos caused lung inflammation in naive rats, whereas pretreatment with an inhibitor of exosomal secretion (GW4869) attenuated HIR-related lung injury. In vivo and in vitro results show that IR-Exos promoted proinflammatory responses and M1 macrophage polarization. Furthermore, miRNA profiling of serum identified miR-122-5p as the exosomal miRNA with the highest increase in young rats with HIR compared with controls. Additionally, IR-Exos transferred miR-122-5p to macrophages and promoted proinflammatory responses and M1 phenotype polarization by targeting suppressor of cytokine signaling protein 1(SOCS-1)/nuclear factor (NF)-κB. Importantly, the pathological role of exosomal miR-122-5p in initiating lung inflammation was reversed by inhibition of miR-122-5p. Clinically, high levels of miR-122-5p were found in serum and correlated to the severity of lung injury in pediatric living-donor liver transplant recipients with ALI. Taken together, our findings reveal that IR-Exos transfer liver-specific miR-122-5p to alveolar macrophages and elicit ALI by inducing M1 macrophage polarization via the SOCS-1/NF-κB signaling pathway.
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Affiliation(s)
- Jingshu Lyu
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China; Department of Anesthesiology and Perioperative Medicine, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial People's Hospital, 450000 Zhengzhou, China
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Yingli Cao
- School of Medicine, Nankai University, 300071 Tianjin, China
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Chen Zhang
- Department of Anesthesiology, The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Yiqi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China
| | - Wenli Yu
- Department of Anesthesiology, Tianjin First Central Hospital, 300192 Tianjin, China; School of Medicine, Nankai University, 300071 Tianjin, China.
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18
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Bongartz H, Bradfield C, Gross J, Fraser I, Nita-Lazar A, Meier-Schellersheim M. IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.28.587272. [PMID: 38654826 PMCID: PMC11037870 DOI: 10.1101/2024.03.28.587272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
During an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.
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Affiliation(s)
- H. Bongartz
- Computational Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - C. Bradfield
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - J. Gross
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - I.D.C. Fraser
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - A. Nita-Lazar
- Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - M. Meier-Schellersheim
- Computational Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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19
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Chen J, Chen Z, Li Y, Wang B, Lu Y, Jian J, Tang J, Cai J. Characterization and functional analysis of SOCS9 from orange-spotted grouper (Epinephelus coioides) during virus infection. FISH & SHELLFISH IMMUNOLOGY 2024; 146:109424. [PMID: 38311091 DOI: 10.1016/j.fsi.2024.109424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/07/2024] [Accepted: 02/02/2024] [Indexed: 02/06/2024]
Abstract
The suppressor of cytokine signaling (SOCS) proteins family have twelve members including eight known mammalian SOCS members (CISH, SOCS1-7) and four new discovery members (SOCS3b, SOCS5b, SOCS8 and SOCS9) that is regarded as a classic feedback inhibitor of cytokine signaling. Although the function of the mammalian SOCS proteins have been well studied, little is known about the roles of SOCS in fish during viral infection. In this study, the molecular characteristics of SOCS9 from orange-spotted grouper (Epinephelus coioides, EcSOCS9) is investigated. The EcSOCS9 protein encoded 543 amino acids with typical SH2 (389-475aa) and SOCS_box (491-527aa), sharing high identities with reported fish SOCS9. EcSOCS9 was expressed in all detected tissues and highly expressed in kidney. After red-spotted grouper nervous necrosis virus (RGNNV) infection, the expression of EcSOCS9 was significantly induced in vitro. Furthermore, EcSOCS9 overexpression enhanced RGNNV replication, promoted virus-induced mitophagy that evidenced by the increased level of LC3-Ⅱ, BCL2, PGAM5 and decreased level of BNIP3 and FUNDC1. Besides, EcSOCS9 overexpression suppressed the expression levels of ATP6, CYB, ND4, ATP level and induced ROS level. The expression levels of interferon (IFN) related factors (IRF1, IRF3, IRF7, P53), inflammatory factors (IL1-β, IL8, TLR2, TNF-α) and IFN-3, ISRE, NF-κB, AP1 activities were also reduced by overexpressing EcSOCS9. These date suggests that EcSOCS9 impacts RGNNV infection through modulating mitophagy, regulating the expression levels of IFN- related and inflammatory factors, which will expand our understanding of fish immune responses during viral infection.
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Affiliation(s)
- Junxi Chen
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Zhaofeng Chen
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Yi Li
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Bei Wang
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Yishan Lu
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Jichang Jian
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Jufen Tang
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China
| | - Jia Cai
- College of Fisheries, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, 524088, PR China; Guangxi Key Laboratory of Aquatic Biotechnology and Modern Ecological Aquaculture, Guangxi Academy of Sciences, Nanning, 530007, PR China.
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20
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Baig MS, Barmpoutsi S, Bharti S, Weigert A, Hirani N, Atre R, Khabiya R, Sharma R, Sarup S, Savai R. Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look. Front Immunol 2024; 15:1355012. [PMID: 38482001 PMCID: PMC10933033 DOI: 10.3389/fimmu.2024.1355012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/22/2024] [Indexed: 04/13/2024] Open
Abstract
Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages' activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.
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Affiliation(s)
- Mirza S. Baig
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Spyridoula Barmpoutsi
- Lung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
| | - Shreya Bharti
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
| | - Nik Hirani
- MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Rajat Atre
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rakhi Khabiya
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rahul Sharma
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Shivmuni Sarup
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rajkumar Savai
- Lung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
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21
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Ilangumaran S, Gui Y, Shukla A, Ramanathan S. SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity. Front Immunol 2024; 15:1362224. [PMID: 38415248 PMCID: PMC10897024 DOI: 10.3389/fimmu.2024.1362224] [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: 12/27/2023] [Accepted: 01/31/2024] [Indexed: 02/29/2024] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.
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Affiliation(s)
- Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Shukla A, Khan MGM, Cayarga AA, Namvarpour M, Chowdhury MMH, Levesque D, Lucier JF, Boisvert FM, Ramanathan S, Ilangumaran S. The Tumor Suppressor SOCS1 Diminishes Tolerance to Oxidative Stress in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:292. [PMID: 38254783 PMCID: PMC10814246 DOI: 10.3390/cancers16020292] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
SOCS1 is a tumor suppressor in hepatocellular carcinoma (HCC). Recently, we showed that a loss of SOCS1 in hepatocytes promotes NRF2 activation. Here, we investigated how SOCS1 expression in HCC cells affected oxidative stress response and modulated the cellular proteome. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). The induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed an increased induction of reactive oxygen species but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. A proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways, including mitochondrial ROS generation and ROS detoxification, through peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.
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Affiliation(s)
- Akhil Shukla
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Md Gulam Musawwir Khan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Anny Armas Cayarga
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Mozhdeh Namvarpour
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Mohammad Mobarak H. Chowdhury
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Dominique Levesque
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Jean-François Lucier
- Department of Biology, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada;
| | - François-Michel Boisvert
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
- Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
- Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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Kandhi R, Yeganeh M, Yoshimura A, Menendez A, Ramanathan S, Ilangumaran S. Hepatic stellate cell-intrinsic role of SOCS1 in controlling hepatic fibrogenic response and the pro-inflammatory macrophage compartment during liver fibrosis. Front Immunol 2023; 14:1259246. [PMID: 37860002 PMCID: PMC10582746 DOI: 10.3389/fimmu.2023.1259246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Introduction Hepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation. Methods Mice lacking SOCS1 in HSCs (Socs1ΔHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated. Results Socs1ΔHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1ΔHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1ΔHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1ΔHSC mice than in Socs1fl/fl mice. Discussion Our findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis.
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Affiliation(s)
- Rajani Kandhi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Mehdi Yeganeh
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Alfredo Menendez
- Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Cheng X, Jiang W, Chen Y, Zou B, Wang Z, Gan L, Xiao Z, Li C, Yu CY, Lu Y, Han Z, Zeng J, Gu J, Chu T, Fu M, Chu Y, Zhang W, Tang J, Lu M. Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance. PLoS Pathog 2023; 19:e1011556. [PMID: 37498977 PMCID: PMC10409266 DOI: 10.1371/journal.ppat.1011556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 08/08/2023] [Accepted: 07/13/2023] [Indexed: 07/29/2023] Open
Abstract
Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.
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Affiliation(s)
- Xiaofang Cheng
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Wei Jiang
- Department of Rheumatology and Immunology, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yeying Chen
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Benkun Zou
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiyan Wang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Lu Gan
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Zeling Xiao
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Changshun Li
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Cheng-Yun Yu
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Yimeng Lu
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Zeyao Han
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Jiashun Zeng
- Department of Rheumatology and Immunology, the Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jie Gu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianqing Chu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mingsheng Fu
- Department of Gastroenterology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Shanghai, China
| | - Wenhong Zhang
- Shanghai Huashen Institute of Microbes and Infections, Shanghai, China
| | - Jianguo Tang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Mingfang Lu
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People’s Hospital, Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Shanghai, China
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Watanabe M, Motooka D, Yamasaki S. The kinetics of signaling through the common FcRγ chain determine cytokine profiles in dendritic cells. Sci Signal 2023; 16:eabn9909. [PMID: 36881655 DOI: 10.1126/scisignal.abn9909] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
The common Fc receptor γ (FcRγ) chain is a signaling subunit common to several immune receptors, but cellular responses induced by FcRγ-coupled receptors are diverse. We investigated the mechanisms by which FcRγ generates divergent signals when coupled to Dectin-2 and Mincle, structurally similar C-type lectin receptors that induce the release of different cytokines from dendritic cells. Chronological tracing of transcriptomic and epigenetic changes upon stimulation revealed that Dectin-2 induced early and strong signaling, whereas Mincle-mediated signaling was delayed, which reflects their expression patterns. Generation of early and strong FcRγ-Syk signaling by engineered chimeric receptors was sufficient to recapitulate a Dectin-2-like gene expression profile. Early Syk signaling selectively stimulated the activity of the calcium ion-activated transcription factor NFAT, which rapidly altered the chromatin status and transcription of the Il2 gene. In contrast, proinflammatory cytokines, such as TNF, were induced regardless of FcRγ signaling kinetics. These results suggest that the strength and timing of FcRγ-Syk signaling can alter the quality of cellular responses through kinetics-sensing signaling machineries.
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Affiliation(s)
- Miyuki Watanabe
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
| | - Daisuke Motooka
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan
| | - Sho Yamasaki
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka 565-0871, Japan.,Division of Molecular Design, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.,Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan
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Pereira M, Gazzinelli RT. Regulation of innate immune signaling by IRAK proteins. Front Immunol 2023; 14:1133354. [PMID: 36865541 PMCID: PMC9972678 DOI: 10.3389/fimmu.2023.1133354] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
The Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) families are of paramount importance in coordinating the early immune response to pathogens. Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). This signaling adaptor forms the scaffold of the myddosome, a molecular platform that employs IL-1R-associated kinase (IRAK) proteins as main players for transducing signals. These kinases are essential in controlling gene transcription by regulating myddosome assembly, stability, activity and disassembly. Additionally, IRAKs play key roles in other biologically relevant responses such as inflammasome formation and immunometabolism. Here, we summarize some of the key aspects of IRAK biology in innate immunity.
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Affiliation(s)
- Milton Pereira
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
| | - Ricardo T. Gazzinelli
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil,Plataforma de Medicina Translacional, Fundação Oswaldo Cruz, Ribeirão Preto, SP, Brazil,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
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Abstract
Innate immunity acts as the first line of defense against pathogen invasion. During Toxoplasma gondii infection, multiple innate immune sensors are activated by invading microbes or pathogen-associated molecular patterns (PAMPs). However, how inflammasome is activated and its regulatory mechanisms during T. gondii infection remain elusive. Here, we showed that the infection of PRU, a lethal type II T. gondii strain, activates inflammasome at the early stage of infection. PRU tachyzoites, RNA and soluble tachyzoite antigen (STAg) mainly triggered the NLRP3 inflammasome, while PRU genomic DNA (gDNA) specially activated the AIM2 inflammasome. Furthermore, mice deficient in AIM2, NLRP3, or caspase-1/11 were more susceptible to T. gondii PRU infection, and the ablation of inflammasome signaling impaired antitoxoplasmosis immune responses by enhancing type I interferon (IFN-I) production. Blockage of IFN-I receptor fulfilled inflammasome-deficient mice competent immune responses as WT mice. Moreover, we have identified that the suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator induced by inflammasome-activated IL-1β signaling and inhibits IFN-I production by targeting interferon regulatory factor 3 (IRF3). In general, our study defines a novel protective role of inflammasome activation during toxoplasmosis and identifies a critical regulatory mechanism of the cross talk between inflammasome and IFN-I signaling for understanding infectious diseases. IMPORTANCE As a key component of innate immunity, inflammasome is critical for host antitoxoplasmosis immunity, but the underlying mechanisms are still elusive. In this study, we found that inflammasome signaling was activated by PAMPs of T. gondii, which generated a protective immunity against T. gondii invasion by suppressing type I interferon (IFN-I) production. Mechanically, inflammasome-coupled IL-1β signaling triggered the expression of negative regulator SOCS1, which bound to IRF3 to inhibit IFN-I production. The role of IFN-I in anti-T. gondii immunity is little studied and controversial, and here we also found IFN-I is harmful to host antitoxoplasmosis immunity by using knockout mice and recombinant proteins. In general, our study identifies a protective role of inflammasomes to the host during T. gondii infection and a novel mechanism by which inflammasome suppresses IFN-I signaling in antitoxoplasmosis immunity, which will likely provide new insights into therapeutic targets for toxoplasmosis and highlight the cross talk between innate immune signaling in infectious diseases prevention.
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Rakib A, Kiran S, Mandal M, Singh UP. MicroRNAs: a crossroad that connects obesity to immunity and aging. Immun Ageing 2022; 19:64. [PMID: 36517853 PMCID: PMC9749272 DOI: 10.1186/s12979-022-00320-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
Obesity is characterized by an elevated amount of fat and energy storage in the adipose tissue (AT) and is believed to be the root cause of many metabolic diseases (MDs). Obesity is associated with low-grade chronic inflammation in AT. Like obesity, chronic inflammation and MDs are prevalent in the elderly. The resident immune microenvironment is not only responsible for maintaining AT homeostasis but also plays a crucial role in stemming obesity and related MDs. Mounting evidence suggests that obesity promotes activation in resident T cells and macrophages. Additionally, inflammatory subsets of T cells and macrophages accumulated into the AT in combination with other immune cells maintain low-grade chronic inflammation. microRNAs (miRs) are small non-coding RNAs and a crucial contributing factor in maintaining immune response and obesity in AT. AT resident T cells, macrophages and adipocytes secrete various miRs and communicate with other cells to create a potential effect in metabolic organ crosstalk. AT resident macrophages and T cells-associated miRs have a prominent role in regulating obesity by targeting several signaling pathways. Further, miRs also emerged as important regulators of cellular senescence and aging. To this end, a clear link between miRs and longevity has been demonstrated that implicates their role in regulating lifespan and the aging process. Hence, AT and circulating miRs can be used as diagnostic and therapeutic tools for obesity and related disorders. In this review, we discuss how miRs function as biomarkers and impact obesity, chronic inflammation, and aging.
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Affiliation(s)
- Ahmed Rakib
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Sonia Kiran
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Mousumi Mandal
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Udai P Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA.
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Wadowska M, Dobosz E, Golda A, Bryzek D, Lech M, Fu M, Koziel J. MCP-Induced Protein 1 Participates in Macrophage-Dependent Endotoxin Tolerance. THE JOURNAL OF IMMUNOLOGY 2022; 209:1348-1358. [DOI: 10.4049/jimmunol.2101184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 07/28/2022] [Indexed: 11/06/2022]
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Duck Tembusu Virus Inhibits Type I Interferon Production through the JOSD1-SOCS1-IRF7 Negative-Feedback Regulation Pathway. J Virol 2022; 96:e0093022. [PMID: 36069544 PMCID: PMC9517709 DOI: 10.1128/jvi.00930-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that mainly causes a decrease in egg production in infected waterfowl. Similar to other members of the Flaviviridae family, it can proliferate in most mammalian cells and may also pose a potential threat to nonavian animals. In previous studies, we found that DTMUV infection can upregulate suppressor of cytokine signaling 1 (SOCS1) to inhibit type I interferon (IFN) production and promote virus replication, but the specific mechanism is unclear. Furthermore, little is known about the regulatory role of ubiquitination during flavivirus infection. In this study, we found that activation of Toll-like receptor 3 (TLR3) signaling rather than type I IFN stimulation led to the upregulation of SOCS1 during DTMUV infection. Further studies revealed that JOSD1 stabilized SOCS1 expression by binding to the SH2 domain of SOCS1 and mediating its deubiquitination. In addition, JOSD1 also inhibited type I IFN production through SOCS1. Finally, SOCS1 acts as an E3 ubiquitin ligase that binds to IFN regulatory factor 7 (IRF7) through its SH2 domain and mediates K48-linked ubiquitination and proteasomal degradation of IRF7, ultimately inhibiting type I IFN production mediated by IRF7 and promoting viral proliferation. These results will enrich and deepen our understanding of the mechanism by which DTMUV antagonizes the host interferon system. IMPORTANCE DTMUV is a newly discovered flavivirus that seriously harms the poultry industry. In recent years, there have been numerous studies on the involvement of ubiquitination in the regulation of innate immunity. However, little is known about the involvement of ubiquitination in the regulation of flavivirus-induced type I IFN signaling. In this study, we found that SOCS1 was induced by TLR3 signaling during DTMUV infection. Furthermore, we found for the first time that duck SOCS1 protein was also modified by K48-linked polyubiquitination, whereas our previous study found that SOCS1 was upregulated during DTMUV infection. Further studies showed that JOSD1 stabilized SOCS1 expression by mediating the deubiquitination of SOCS1. While SOCS1 acts as a negative regulator of cytokines, we found that DTMUV utilized SOCS1 to mediate the ubiquitination and proteasomal degradation of IRF7 and ultimately inhibit type I IFN production, thereby promoting its proliferation.
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Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease. Mediators Inflamm 2022; 2022:7924199. [PMID: 36046763 PMCID: PMC9420645 DOI: 10.1155/2022/7924199] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/18/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily manifests as memory deficits and cognitive impairment and has created health challenges for patients and society. In AD, amyloid β-protein (Aβ) induces Toll-like receptor 4 (TLR4) activation in microglia. Activation of TLR4 induces downstream signaling pathways and promotes the generation of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), which also trigger the activation of astrocytes and influence amyloid-dependent neuronal death. Therefore, TLR4 may be an important molecular target for treating AD by regulating neuroinflammation. Moreover, TLR4 regulates apoptosis, autophagy, and gut microbiota and is closely related to AD. This article reviews the role of TLR4 in the pathogenesis of AD and a range of potential therapies targeting TLR4 for AD. Elucidating the regulatory mechanism of TLR4 in AD may provide valuable clues for developing new therapeutic strategies for AD.
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Kopalli SR, Annamneedi VP, Koppula S. Potential Natural Biomolecules Targeting JAK/STAT/SOCS Signaling in the Management of Atopic Dermatitis. Molecules 2022; 27:molecules27144660. [PMID: 35889539 PMCID: PMC9319717 DOI: 10.3390/molecules27144660] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 12/29/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by the dysregulation of cytokines and other immune mediators. JAK/STAT is a classical signal transduction pathway involved in various biological processes, and its dysregulation contributes to the key aspects of AD pathogenesis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the immune-related inflammatory responses mediated by the JAK/STAT pathway. JAK/STAT-mediated production of cytokines including IL-4, IL-13, IL-31, and TSLP inhibits the expression of important skin barrier proteins and triggers pruritus in AD. The expression of SOCS proteins regulates the JAK-mediated cytokines and facilitates maintaining the skin barrier disruptions seen in AD. STATs are crucial in dendritic-cell-activated Th2 cell differentiation in the skin, releasing inflammatory cytokines, indicating that AD is a Th2-mediated skin disorder. SOCS proteins aid in balancing Th1/Th2 cells and, moreover, regulate the onset and maintenance of Th2-mediated allergic responses by reducing the Th2 cell activation and differentiation. SOCS proteins play a pivotal role in inflammatory cytokine-signaling events that act via the JAK/STAT pathway. Therapies relying on natural products and derived biomolecules have proven beneficial in AD when compared with the synthetic regimen. In this review, we focused on the available literature on the potential natural-product-derived biomolecules targeting JAK/STAT/SOCS signaling, mainly emphasizing the SOCS family of proteins (SOCS1, SOCS3, and SOCS5) acting as negative regulators in modulating JAK/STAT-mediated responses in AD pathogenesis and other inflammatory disorders.
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Affiliation(s)
| | - Venkata Prakash Annamneedi
- Convergence Science Research Center, College of Pharmacy and Institute of Chronic Diseases, Sahmyook University, Seoul 01795, Korea;
| | - Sushruta Koppula
- Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju 27381, Korea
- Correspondence:
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33
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022. [PMID: 35309296 DOI: 10.3389/fimmu.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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34
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Sheu KM, Hoffmann A. Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance. Annu Rev Immunol 2022; 40:295-321. [PMID: 35471841 PMCID: PMC10074967 DOI: 10.1146/annurev-immunol-101320-031555] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.
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Affiliation(s)
- Katherine M Sheu
- Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA;
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA;
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35
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022; 13:812774. [PMID: 35309296 PMCID: PMC8927970 DOI: 10.3389/fimmu.2022.812774] [Citation(s) in RCA: 425] [Impact Index Per Article: 141.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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36
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Zhao L, Li J, Zhou X, Pan Q, Zhao W, Yang X, Wang H. Natural Killer Cells Regulate Pulmonary Macrophages Polarization in Host Defense Against Chlamydial Respiratory Infection. Front Cell Infect Microbiol 2022; 11:775663. [PMID: 35059323 PMCID: PMC8764407 DOI: 10.3389/fcimb.2021.775663] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/07/2021] [Indexed: 12/22/2022] Open
Abstract
NK cells and pulmonary macrophages both are important components of innate immunity. The interaction between NK cells and pulmonary macrophages during chlamydial infection is poorly understood. In this study, we explored the effect of NK cells on regulation of pulmonary macrophage function during chlamydial respiratory infection. We found that NK depletion led to polarization of pulmonary macrophages from M1 to M2 phenotype, and it is related to reduced miR-155 expression in lung macrophage. Using adoptive transfer approach, we found that the recipients receiving lung macrophages isolated from C. muridarum-infected NK-cell-depleted mice exhibited an increased bacterial load and severe inflammation in the lung upon chlamydial challenge infection when compared with the recipients of lung macrophages from infected isotype control antibody treated mice. Herein, the effects of NK cells on macrophage polarization were examined in vitro. We found that NK cells from chlamydial-infected mice (iNK) significantly induced M1 polarization compared to that from uninfected mice (uNK). Inhibition of miR-155 expression in macrophages reduced M1 polarization induced by iNK, while miR-155 over-expression enhanced it. Furthermore, neutralization of IFN-γ in the coculture system decreased the expression of miR-155 by macrophages, and resulted in weakened M1 polarization. The data indicates that NK cells promote M1 polarization through up-regulation of miR-155 in macrophages by producing IFN-γ during chlamydial infection, and NK-regulated macrophage polarization is functionally relevant to host defense against the infection.
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Affiliation(s)
- Lei Zhao
- Laboratory of Basic Medical Science, Qilu Hospital of Shandong University, Jinan, China
| | - Jing Li
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.,Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xiaoqing Zhou
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Qianqian Pan
- Department of Respiratory, Laiwu Central Hospital, Jinan, China
| | - Weiming Zhao
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xi Yang
- Departments of Immunology and Medical Microbiology and Infectious Diseases, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Hong Wang
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
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37
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Jeong H, Yoon H, Lee Y, Kim JT, Yang M, Kim G, Jung B, Park SH, Lee CE. SOCS3 Attenuates Dexamethasone-Induced M2 Polarization by Down-Regulation of GILZ via ROS- and p38 MAPK-Dependent Pathways. Immune Netw 2022; 22:e33. [PMID: 36081527 PMCID: PMC9433193 DOI: 10.4110/in.2022.22.e33] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 05/17/2022] [Accepted: 06/02/2022] [Indexed: 12/31/2022] Open
Abstract
Suppressors of cytokine signaling (SOCS) have emerged as potential regulators of macrophage function. We have investigated mechanisms of SOCS3 action on type 2 macrophage (M2) differentiation induced by glucocorticoid using human monocytic cell lines and mouse bone marrow-derived macrophages. Treatment of THP1 monocytic cells with dexamethasone (Dex) induced ROS generation and M2 polarization promoting IL-10 and TGF-β production, while suppressing IL-1β, TNF-α and IL-6 production. SOCS3 over-expression reduced, whereas SOCS3 ablation enhanced IL-10 and TGF-β induction with concomitant regulation of ROS. As a mediator of M2 differentiation, glucocorticoid-induced leucine zipper (GILZ) was down-regulated by SOCS3 and up-regulated by shSOCS3. The induction of GILZ and IL-10 by Dex was dependent on ROS and p38 MAPK activity. Importantly, GILZ ablation led to the inhibition of ROS generation and anti-inflammatory cytokine induction by Dex. Moreover, GILZ knock-down negated the up-regulation of IL-10 production induced by shSOCS3 transduction. Our data suggest that SOCS3 targets ROS- and p38-dependent GILZ expression to suppress Dex-induced M2 polarization.
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Affiliation(s)
- Hana Jeong
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Hyeyoung Yoon
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Yerin Lee
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Jun Tae Kim
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Moses Yang
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Gayoung Kim
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Bom Jung
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Seok Hee Park
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Choong-Eun Lee
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
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38
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Larsson L, Garaicoa-Pazmino C, Asa'ad F, Castilho RM. Understanding the role of endotoxin tolerance in chronic inflammatory conditions and periodontal disease. J Clin Periodontol 2021; 49:270-279. [PMID: 34970759 DOI: 10.1111/jcpe.13591] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This review aims to present the current understanding of endotoxin tolerance (ET) in chronic inflammatory diseases and explores the potential connection with periodontitis. SUMMARY Subsequent exposure to lipopolysaccharides (LPS) triggers ET, a phenomenon regulated by different mechanisms and pathways, including toll-like receptors (TLRs), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), apoptosis of immune cells, epigenetics, and microRNAs (miRNAs). These mechanisms interconnect ET with chronic inflammatory diseases that include periodontitis. While the direct correlation between ET and periodontal destruction has not been fully elucidated, emerging reports point towards the potential tolerization of human periodontal ligament cells (hPDLCs) and gingival tissues with a significant reduction of TLR levels. CONCLUSIONS There is a potential link between ET and periodontal diseases. Future studies should explore the crucial role of ET in the pathogenesis of periodontal diseases as evidence of a tolerized oral mucosa may represent an intrinsic mechanism capable of regulating the oral immune response. A clear understanding of this host immune regulatory mechanism might lead to effective and more predictable therapeutic strategies to treat chronic inflammatory diseases and periodontitis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Lena Larsson
- Department of Periodontology Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Carlos Garaicoa-Pazmino
- Department of Periodontics, University of Iowa, College of Dentistry and Dental Clinics, Iowa City, IA, USA.,School of Dentistry, Espíritu Santo University, Samborondon, Ecuador
| | - Farah Asa'ad
- Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.,Department of Oral Biochemistry, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Rogerio M Castilho
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.,Laboratory of Epithelial Biology, University of Michigan School of Dentistry, Ann Arbor, MI, USA
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Balkrishna A, Lochab S, Joshi M, Srivastava J, Varshney A. Divya-Herbal-Peya Decoction Harmonizes the Inflammatory Response in Lipopolysaccharide-Induced Zebrafish Model. J Exp Pharmacol 2021; 13:937-955. [PMID: 34880683 PMCID: PMC8648330 DOI: 10.2147/jep.s328864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 11/02/2021] [Indexed: 11/30/2022] Open
Abstract
Background Divya-Herbal-Peya (DHP) is a plant-based decoction containing fourteen herbs in precise quantities; usually prescribed by the practitioners in Ayurveda to alleviate stress and minimize the exasperating symptoms of recurring infections. Our study aims to provide an experimental validation to the immunomodulatory properties of DHP. Methods Physico-chemical analysis of DHP was performed to evaluate the presence of secondary metabolites. The phytochemicals were then identified and quantitated through HPTLC, UHPLC, and GC-MS techniques. To address the scientific rationale behind DHP, lipopolysaccharide (LPS) was intraperitoneally injected in adult zebrafish to develop inflammatory response. Following LPS-induction, abnormality in locomotory behaviour was determined by evaluating the relative swim velocity and the rate of turning in experimental zebrafish. Pathophysiological effects were determined through opercular frequency, behavioural fever, and caudal fin damage. LPS-mediated inflammation was measured of pro-inflammatory cytokines, TNFα, IL-6, and IL-1β expression in the serum of study animals, by RT-PCR. Results Our study phytochemically characterized and ascertained the presence of glycyrrhizin, rosmarinic acid, gingerol, cinnamic acid, protocatechuic acid, gallic acid, ellagic acid, piperine and cinnamaldehyde in DHP decoction. LPS induced aberrant locomotory patterns, behavioural fever and caudal fin damage in zebrafish. A significant increase in gene expression levels of pro-inflammatory cytokines, TNFα, IL-6, and IL-1β was also determined. However, these locomotory deviations and behavioural fever were negligible in zebrafish groups pre-administered either with DHP in a dose dependent manner or dexamethasone (DEX). The altered opercular rate, caudal fin damage and elevated transcription levels of pro-inflammatory genes upon LPS-induction were averted in groups pre-treated with DHP and DEX. Conclusion DHP prophylactically prevented the LPS-induced abnormal behaviour and inflammation-related pathophysiology in zebrafish. Immunomodulatory properties of DHP may not have therapeutic intervention, but do confer nutraceutical health benefits against mild infections.
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Affiliation(s)
- Acharya Balkrishna
- Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.,Department of Allied and Applied Sciences, University of Patanjali, Patanjali Yog Peeth, Haridwar, 249405, Uttarakhand, India.,Patanjali Yog Peeth (UK) Trust, Glasgow, G41 1AU, UK
| | - Savita Lochab
- Department of Biology, Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India
| | - Monali Joshi
- Department of Chemistry, Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India
| | - Jyotish Srivastava
- Department of Chemistry, Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India
| | - Anurag Varshney
- Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.,Department of Allied and Applied Sciences, University of Patanjali, Patanjali Yog Peeth, Haridwar, 249405, Uttarakhand, India.,Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
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40
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Zhang T, Ma C, Zhang Z, Zhang H, Hu H. NF-κB signaling in inflammation and cancer. MedComm (Beijing) 2021; 2:618-653. [PMID: 34977871 PMCID: PMC8706767 DOI: 10.1002/mco2.104] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 02/06/2023] Open
Abstract
Since nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB) was discovered in 1986, extraordinary efforts have been made to understand the function and regulating mechanism of NF-κB for 35 years, which lead to significant progress. Meanwhile, the molecular mechanisms regulating NF-κB activation have also been illuminated, the cascades of signaling events leading to NF-κB activity and key components of the NF-κB pathway are also identified. It has been suggested NF-κB plays an important role in human diseases, especially inflammation-related diseases. These studies make the NF-κB an attractive target for disease treatment. This review aims to summarize the knowledge of the family members of NF-κB, as well as the basic mechanisms of NF-κB signaling pathway activation. We will also review the effects of dysregulated NF-κB on inflammation, tumorigenesis, and tumor microenvironment. The progression of the translational study and drug development targeting NF-κB for inflammatory diseases and cancer treatment and the potential obstacles will be discussed. Further investigations on the precise functions of NF-κB in the physiological and pathological settings and underlying mechanisms are in the urgent need to develop drugs targeting NF-κB for inflammatory diseases and cancer treatment, with minimal side effects.
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Affiliation(s)
- Tao Zhang
- Cancer Center and Center for Immunology and HematologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Chao Ma
- Cancer Center and Center for Immunology and HematologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Zhiqiang Zhang
- Immunobiology and Transplant Science CenterHouston Methodist HospitalHoustonTexasUSA
| | - Huiyuan Zhang
- Cancer Center and Center for Immunology and HematologyWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongbo Hu
- Cancer Center and Center for Immunology and HematologyWest China HospitalSichuan UniversityChengduSichuanChina
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41
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Hey J, Paulsen M, Toth R, Weichenhan D, Butz S, Schatterny J, Liebers R, Lutsik P, Plass C, Mall MA. Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease. Nat Commun 2021; 12:6520. [PMID: 34764283 PMCID: PMC8586227 DOI: 10.1038/s41467-021-26777-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
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Affiliation(s)
- Joschka Hey
- grid.7497.d0000 0004 0492 0584Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Ruprecht Karl University of Heidelberg, Heidelberg, Germany ,grid.452624.3Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Michelle Paulsen
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany. .,Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany. .,Novo Nordisk Foundation Center for Stem Cell Biology, University of Copenhagen, Copenhagen, Denmark.
| | - Reka Toth
- grid.7497.d0000 0004 0492 0584Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dieter Weichenhan
- grid.7497.d0000 0004 0492 0584Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Simone Butz
- grid.452624.3Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany
| | - Jolanthe Schatterny
- grid.452624.3Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany
| | - Reinhard Liebers
- grid.7497.d0000 0004 0492 0584Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.461742.2Present Address: National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Pavlo Lutsik
- grid.7497.d0000 0004 0492 0584Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christoph Plass
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
| | - Marcus A. Mall
- grid.452624.3Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany ,grid.7468.d0000 0001 2248 7639Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany ,grid.484013.aBerlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany ,grid.452624.3German Center for Lung Research (DZL), Associated Partner, Berlin, Germany
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42
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Yan D, Earp HS, DeRyckere D, Graham DK. Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer. Cancers (Basel) 2021; 13:5639. [PMID: 34830794 PMCID: PMC8616094 DOI: 10.3390/cancers13225639] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/20/2022] Open
Abstract
MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.
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Affiliation(s)
- Dan Yan
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
| | - H. Shelton Earp
- UNC Lineberger Comprehensive Cancer Center, Department of Medicine, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Deborah DeRyckere
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
| | - Douglas K. Graham
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
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Zubair K, You C, Kwon G, Kang K. Two Faces of Macrophages: Training and Tolerance. Biomedicines 2021; 9:biomedicines9111596. [PMID: 34829825 PMCID: PMC8615871 DOI: 10.3390/biomedicines9111596] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 01/16/2023] Open
Abstract
Macrophages are present in almost all body tissues. They detect and quickly respond to “environmental signals” in the tissue. Macrophages have been associated with numerous beneficial roles, such as host defense, wound healing, and tissue regeneration; however, they have also been linked to the development of diverse illnesses, particularly cancers and autoimmune disorders. Complex signaling, epigenetic, and metabolic pathways drive macrophage training and tolerance. The induced intracellular program differs depending on the type of initial stimuli and the tissue microenvironment. Due to the essential roles of macrophages in homeostatic and their association with the pathogenesis of inflammatory diseases, recent studies have investigated the molecular mechanisms of macrophage training and tolerance. This review discusses the role of factors involved in macrophage training and tolerance, along with the current studies in human diseases.
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Sobah ML, Liongue C, Ward AC. SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer. Front Med (Lausanne) 2021; 8:727987. [PMID: 34604264 PMCID: PMC8481645 DOI: 10.3389/fmed.2021.727987] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/16/2021] [Indexed: 01/10/2023] Open
Abstract
Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
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Affiliation(s)
| | - Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
| | - Alister C Ward
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
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Wu C, Deng H, Li D, Fan L, Yao D, Zhi X, Mao H, Hu C. Ctenopharyngodon idella Tollip regulates MyD88-induced NF-κB activation. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 123:104162. [PMID: 34090930 DOI: 10.1016/j.dci.2021.104162] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/30/2021] [Accepted: 05/30/2021] [Indexed: 06/12/2023]
Abstract
Toll-interacting protein (Tollip) and MyD88 are key components of the TLR/IL-1R signaling pathway in mammals. MyD88 is known as a universal adaptor protein involving in TLR/IL-1R-induced NF-κB activation. Tollip is a crucial negative regulator of TLR-mediated innate immune responses. Previous studies have demonstrated that teleost Tollip served as a negative regulator of MyD88-dependent TLR signaling pathway. However, the mechanism is still unclear. In particular, the effect of TBD, C2, and CUE domains of Tollip on MyD88-NF-κB signaling pathway remains to be elucidated. In this study, we found that the response of grass carp Tollip (CiTollip) to LPS stimulation was faster and stronger than that of poly I:C treatment, and CiTollip diminished the expression of tnf-α induced by LPS. Further assays indicated that except for the truncated mutant of △CUE2 (1-173 aa), wild type CiTollip and other truncated mutants (△N-(52-276 aa), △C2-(173-276 aa) and △CUE1-(1-231 aa)) could associate with MyD88 and negatively regulate MyD88-induced NF-κB activation. It suggested that the C-terminal (173-276 aa), in particular the connection section between C2 and CUE domains (173-231 aa), played a pivotal role in suppressing MyD88-induced activation of NF-κB.
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Affiliation(s)
- Chuxin Wu
- Yuzhang Normal University, Nanchang, 330103, China
| | - Hang Deng
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Dongming Li
- Fuzhou Medical College, Nanchang University, Fuzhou, 344000, China
| | - Lihua Fan
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Dong Yao
- Yuzhang Normal University, Nanchang, 330103, China
| | - Xiaoping Zhi
- Yuzhang Normal University, Nanchang, 330103, China
| | - Huiling Mao
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China
| | - Chengyu Hu
- Department of Bioscience, College of Life Science, Nanchang University, Nanchang, 330031, China.
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Kim GY, Jeong H, Yoon HY, Yoo HM, Lee JY, Park SH, Lee CE. Anti-inflammatory mechanisms of suppressors of cytokine signaling target ROS via NRF-2/thioredoxin induction and inflammasome activation in macrophages. BMB Rep 2021. [PMID: 33172542 PMCID: PMC7781909 DOI: 10.5483/bmbrep.2020.53.12.161] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Suppressors of cytokine signaling (SOCS) exhibit diverse anti-inflammatory effects. Since ROS acts as a critical mediator of inflammation, we have investigated the anti-inflammatory mechanisms of SOCS via ROS regulation in monocytic/macrophagic cells. Using PMA-differentiated monocytic cell lines and primary BMDMs transduced with SOCS1 or shSOCS1, the LPS/TLR4-induced inflammatory signaling was investigated by analyzing the levels of intracellular ROS, antioxidant factors, inflammasome activation, and pro-inflammatory cytokines. The levels of LPS-induced ROS and the production of pro-inflammatory cytokines were notably down-regulated by SOCS1 and up-regulated by shSOCS1 in an NAC-sensitive manner. SOCS1 up-regulated an ROS-scavenging protein, thioredoxin, via enhanced expression and binding of NRF-2 to the thioredoxin promoter. SOCS3 exhibited similar effects on NRF-2/thioredoxin induction, and ROS downregulation, resulting in the suppression of inflammatory cytokines. Notably thioredoxin ablation promoted NLRP3 inflammasome activation and restored the SOCS1-mediated inhibition of ROS and cytokine synthesis induced by LPS. The results demonstrate that the anti-inflammatory mechanisms of SOCS1 and SOCS3 in macrophages are mediated via NRF-2-mediated thioredoxin upregulation resulting in the downregulation of ROS sig-nal. Thus, our study supports the anti-oxidant role of SOCS1 and SOCS3 in the exquisite regulation of macrophage activation under oxidative stress.
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Affiliation(s)
- Ga-Young Kim
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Hana Jeong
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Hye-Young Yoon
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Hye-Min Yoo
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Jae Young Lee
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Seok Hee Park
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
| | - Choong-Eun Lee
- Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, Korea
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Zaman A, Bivona TG. Targeting AXL in NSCLC. LUNG CANCER (AUCKLAND, N.Z.) 2021; 12:67-79. [PMID: 34408519 PMCID: PMC8364399 DOI: 10.2147/lctt.s305484] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022]
Abstract
State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL's role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL's role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.
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Affiliation(s)
- Aubhishek Zaman
- Department of Medicine, University of California, San Francisco, CA, USA
- UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Trever G Bivona
- Department of Medicine, University of California, San Francisco, CA, USA
- UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
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Shi Y, Chen G, Teng J. Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury. Front Mol Biosci 2021; 8:655361. [PMID: 34262937 PMCID: PMC8273177 DOI: 10.3389/fmolb.2021.655361] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/07/2021] [Indexed: 12/15/2022] Open
Abstract
Acute kidney injury (AKI) is a severe and frequently observed condition associated with high morbidity and mortality. The molecular mechanisms underlying AKI have not been elucidated due to the complexity of the pathophysiological processes. Thus, we investigated the key biological molecules contributing to AKI based on the transcriptome profile. We analyzed the RNA sequencing data from 39 native human renal biopsy samples and 9 reference nephrectomies from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and Gene Ontology (GO) analysis revealed that various GO terms were dysregulated in AKI. Gene set enrichment analysis (GSEA) highlighted dysregulated pathways, including "DNA replication," "chemokine signaling pathway," and "metabolic pathways." Furthermore, the protein-to-protein interaction (PPI) networks of the DEGs were constructed, and the hub genes were identified using Cytoscape. Moreover, weighted gene co-expression network analysis (WGCNA) was performed to validate the DEGs in AKI-related modules. Subsequently, the upregulated hub genes STUB1, SOCS1, and VHL were validated as upregulated in human AKI and a mouse cisplatin-induced AKI model. Moreover, the biological functions of STUB1 were investigated in renal tubular epithelial cells. Cisplatin treatment increased STUB1 expression in a dose-dependent manner at both the mRNA and protein levels. Knockdown of STUB1 by siRNA increased the expression of proapoptotic Bax and cleaved caspase-3 while decreasing antiapoptotic Bcl-2. In addition, silencing STUB1 increased the apoptosis of HK-2 cells and the proinflammatory cytokine production of IL6, TNFα, and IL1β induced by cisplatin. These results indicated that STUB1 may contribute to the initiation and progression of AKI by inducing renal tubular epithelial cell apoptosis and renal inflammation.
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Affiliation(s)
- Yanting Shi
- Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Genwen Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Teng
- Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
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Karki P, Cha B, Zhang CO, Li Y, Ke Y, Promnares K, Kaibuchi K, Yoshimura A, Birukov KG, Birukova AA. Microtubule-dependent mechanism of anti-inflammatory effect of SOCS1 in endothelial dysfunction and lung injury. FASEB J 2021; 35:e21388. [PMID: 33724556 PMCID: PMC10069762 DOI: 10.1096/fj.202001477rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 12/21/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Abstract
Suppressors of cytokine signaling (SOCS) provide negative regulation of inflammatory reaction. The role and precise cellular mechanisms of SOCS1 in control of endothelial dysfunction and barrier compromise associated with acute lung injury remain unexplored. Our results show that siRNA-mediated SOCS1 knockdown augmented lipopolysaccharide (LPS)-induced pulmonary endothelial cell (EC) permeability and enhanced inflammatory response. Consistent with in vitro data, EC-specific SOCS1 knockout mice developed more severe lung vascular leak and accumulation of inflammatory cells in bronchoalveolar lavage fluid. SOCS1 overexpression exhibited protective effects against LPS-induced endothelial permeability and inflammation, which were dependent on microtubule (MT) integrity. Biochemical and image analysis of unstimulated EC showed SOCS1 association with the MT, while challenge with LPS or MT depolymerizing agent colchicine impaired this association. SOCS1 directly interacted with N2 domains of MT-associated proteins CLIP-170 and CLASP2. Furthermore, N-terminal region of SOCS1 was indispensable for these interactions and SOCS1-ΔN mutant lacking N-terminal 59 amino acids failed to rescue LPS-induced endothelial dysfunction. Depletion of endogenous CLIP-170 or CLASP2 abolished SOCS1 interaction with Toll-like receptor-4 and Janus kinase-2 leading to impairment of SOCS1 inhibitory effects on LPS-induced inflammation. Altogether, these findings suggest that endothelial barrier protective and anti-inflammatory effects of SOCS1 are critically dependent on its targeting to the MT.
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Affiliation(s)
- Pratap Karki
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Boyoung Cha
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Chen-Ou Zhang
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yue Li
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yunbo Ke
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kamoltip Promnares
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Nagoya University, Nagoya, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University, Tokyo, Japan
| | - Konstantin G Birukov
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Anna A Birukova
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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50
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El-Sahar AE, Shiha NA, El Sayed NS, Ahmed LA. Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways. Int J Neuropsychopharmacol 2021; 24:158-169. [PMID: 33125461 PMCID: PMC7883892 DOI: 10.1093/ijnp/pyaa078] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/03/2020] [Accepted: 10/28/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. METHODS Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL). RESULTS Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. CONCLUSION The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.
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Affiliation(s)
- Ayman E El-Sahar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nesma A Shiha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nesrine S El Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Lamiaa A Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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