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Tian G, Chen Z, Wang B, Chen G, Xie L. Small-molecule BTK inhibitors: From discovery to clinical application. Bioorg Chem 2025; 157:108242. [PMID: 39922043 DOI: 10.1016/j.bioorg.2025.108242] [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: 01/17/2025] [Revised: 01/29/2025] [Accepted: 02/02/2025] [Indexed: 02/10/2025]
Abstract
Bruton's tyrosine kinase (BTK) inhibitors constitute a promising category of small molecules for the therapy of diverse B-cell malignancies and autoimmune disorders. This review examines the journey of BTK inhibitors from their discovery to clinical development, highlighting key milestones in their design, mechanism of action, and progression through preclinical and clinical stages. Initially identified through high-throughput screening of compound libraries, early BTK inhibitors were optimized for selectivity and potency. The discovery of ibrutinib, the first Food and Drug Administration (FDA)-approved BTK inhibitor, marked a significant breakthrough, providing a new therapeutic option for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Following this success, numerous second-generation inhibitors have been identified to address resistance mechanisms, improve pharmacokinetics, and target specific patient populations. The challenges faced during the transition from preclinical validation to clinical trials have been discussed. Additionally, ongoing trials and emerging data on novel BTK inhibitors provide insights into their evolving role in oncology and immunology. This review emphasizes the importance of rational drug design and clinical strategy in shaping the future of BTK inhibitors.
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Affiliation(s)
- Gengren Tian
- Department of Neurosurgery China-Japan Union Hospital of Jilin University Changchun China
| | - Zhuo Chen
- Department of Neurosurgery China-Japan Union Hospital of Jilin University Changchun China
| | - Baizhi Wang
- Department of Emergency Weifang People's Hospital WeiFang China
| | - Guangyong Chen
- Department of Neurosurgery China-Japan Union Hospital of Jilin University Changchun China.
| | - Lijuan Xie
- Department of Vascularsurgery China-Japan Union Hospital of Jilin University Changchun China.
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2
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Gupta S, Sharma A, Shukla A, Mishra A, Singh A. From development to clinical success: the journey of established and next-generation BTK inhibitors. Invest New Drugs 2025:10.1007/s10637-025-01513-y. [PMID: 40014234 DOI: 10.1007/s10637-025-01513-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/30/2025] [Indexed: 02/28/2025]
Abstract
Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.
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Affiliation(s)
- Shivani Gupta
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, IIT (BHU), Varanasi, 221005, India
| | - Arpit Sharma
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, IIT (BHU), Varanasi, 221005, India
| | - Alok Shukla
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, IIT (BHU), Varanasi, 221005, India
| | - Abha Mishra
- Biomolecular Engineering Laboratory, School of Biochemical Engineering, IIT (BHU), Varanasi, 221005, India.
| | - Amit Singh
- Department of Pharmacology, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India.
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3
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Aomine Y, Shimo Y, Sakurai K, Abe M, Macpherson T, Ozawa T, Hikida T. Sex-dependent differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice. J Neurochem 2025; 169:e16227. [PMID: 39289039 DOI: 10.1111/jnc.16227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 08/20/2024] [Accepted: 09/01/2024] [Indexed: 09/19/2024]
Abstract
Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein-protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex-dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.
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Affiliation(s)
- Yoshiatsu Aomine
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Research Fellow of Japan Society for the Promotion of Science, Suita, Japan
| | - Yuto Shimo
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
| | - Koki Sakurai
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
- Laboratory of Protein Profiling and Functional Proteomics, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Mayuka Abe
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
| | - Tom Macpherson
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
| | - Takaaki Ozawa
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
| | - Takatoshi Hikida
- Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan
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4
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Ding Q, Zhou Y, Feng Y, Sun L, Zhang T. Bruton's tyrosine kinase: A promising target for treating systemic lupus erythematosus. Int Immunopharmacol 2024; 142:113040. [PMID: 39216117 DOI: 10.1016/j.intimp.2024.113040] [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: 07/08/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder involving multiple organs and systems. There is growing evidence that autoreactive B cells occupy a central role in the occurrence and progression of SLE due to their ability to generate pathogenic autoantibodies. Small molecule inhibitors targeting Bruton's tyrosine kinase (BTK), a crucial intracellular kinase regulating B cell development and function, emerge as a new strategy to treat SLE in recent years and are superior to biologic agents depleting B cells in many aspects. Supportive data obtained from lupus-prone mice preliminarily demonstrated the promising therapeutic potential of BTK inhibition. However, these BTK inhibitors, including elsubrutinib, evobrutinib, etc., mostly face with unsatisfactory efficacy and certain safety issues during clinical use, driving the quest for new-generation inhibitors with improved potency and higher selectivity. This paper elaborates the importance of BTK involvement in SLE pathogenesis, reviews the clinical research progress of BTK inhibitors for SLE and discusses limitations and challenges the drugs met in development, in order to contribute to a deeper understanding of disease mechanism and provide a reference for new-generation BTK inhibitor research.
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Affiliation(s)
- Qiaoyi Ding
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yu Zhou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yifan Feng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Lan Sun
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Tiantai Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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5
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Rumford JE, Grieshaber A, Lewiston S, Reed JL, Long SS, Mitchell DM. Forced MyD88 signaling in microglia impacts the production and survival of regenerated retinal neurons. Front Cell Dev Biol 2024; 12:1495586. [PMID: 39633708 PMCID: PMC11614808 DOI: 10.3389/fcell.2024.1495586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024] Open
Abstract
Inflammation and microglia appear to be key factors influencing the outcome of retinal regeneration following acute retinal damage. Despite such findings, direct connection of microglia-specific inflammatory factors as drivers of regenerative responses in the retina are still not defined, and intracellular pathways activated to stimulate such signals from microglia are currently unknown. We became interested in MyD88 regulation in microglia because transcriptomic datasets suggest myd88 could be regulated temporally in zebrafish microglia responding to damage in the central nervous system. MyD88 is an intracellular molecular adaptor that initiates signaling cascades downstream of several innate immune receptors, and probably most well-known for inducing gene expression of pro-inflammatory factors. Using zebrafish, which spontaneously regenerate retinal neurons after acute retinal damage, we studied the effects of overactivation of MyD88 signaling in microglia and macrophages on the Müller glia-mediated regenerative response. Our results indicate that increased MyD88 signaling in microglia/macrophages impacts the initial response of Müller glia entering a regenerative response after acute, neurotoxin-induced retinal damage to inner retinal neurons. In addition, increased MyD88 signaling in microglia/macrophages resulted in reduced survival of inner retinal neurons in regenerated retinas. This work supports the idea that temporal control of inflammatory signaling is a key component in the production of MG-derived progenitors yet further indicates that such control is important for differentiation and survival of regenerated neurons.
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Affiliation(s)
- Jordan E. Rumford
- Department of Biological Sciences, University of Idaho, Moscow, ID, United States
| | - Ailis Grieshaber
- Department of Biological Sciences, University of Idaho, Moscow, ID, United States
| | - Samantha Lewiston
- Department of Biological Sciences, University of Idaho, Moscow, ID, United States
| | - Jordan L. Reed
- Department of Computer Science, University of Idaho, Moscow, ID, United States
- Formerly North Idaho College, Coeur d’Alene, ID, United States
| | - Samuel S. Long
- Business and Computer Science Division, Lewis-Clark State College, Lewiston, ID, United States
| | - Diana M. Mitchell
- Department of Biological Sciences, University of Idaho, Moscow, ID, United States
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Zhang Y, Gao Y, Wang Y, Jiang Y, Xiang Y, Wang X, Wang Z, Ding Y, Chen H, Rui B, Huai W, Cai B, Ren X, Ma F, Xu S, Zhan Z, Liu X. RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring. Cell Mol Immunol 2024; 21:1231-1250. [PMID: 39251781 PMCID: PMC11527992 DOI: 10.1038/s41423-024-01212-3] [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: 12/03/2023] [Accepted: 08/21/2024] [Indexed: 09/11/2024] Open
Abstract
Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.
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MESH Headings
- Animals
- Inflammation/pathology
- Inflammation/genetics
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Mice
- RNA Splicing/genetics
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/immunology
- Macrophages/metabolism
- Macrophages/immunology
- Humans
- ATP Citrate (pro-S)-Lyase/metabolism
- ATP Citrate (pro-S)-Lyase/genetics
- Mice, Inbred C57BL
- Mice, Knockout
- Spliceosomes/metabolism
- Arthritis, Experimental/pathology
- Arthritis, Experimental/immunology
- Arthritis, Experimental/genetics
- Arthritis, Experimental/metabolism
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Affiliation(s)
- Yunkai Zhang
- Naval Medical Center, Naval Medical University, Shanghai, 200433, China
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Ying Gao
- Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yujia Wang
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yuyu Jiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Yan Xiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Xiaohui Wang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Zeting Wang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Yingying Ding
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Huiying Chen
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Bing Rui
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Wanwan Huai
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Boyu Cai
- Department of Otolaryngology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Xiaomeng Ren
- Naval Medical Center, Naval Medical University, Shanghai, 200433, China
| | - Feng Ma
- Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, China
| | - Sheng Xu
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhenzhen Zhan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Xingguang Liu
- National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China.
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China.
- Key Laboratory of Biological Defense, Ministry of Education, Shanghai, 200433, China.
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Jiang Q, Peng Y, Herling CD, Herling M. The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond. Cancers (Basel) 2024; 16:3574. [PMID: 39518015 PMCID: PMC11545099 DOI: 10.3390/cancers16213574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a pivotal role in B cell biology and function. As an essential component of the B cell receptor (BCR) signaling pathway, BTK is expressed not only in B cells but also in myeloid cells, including monocytes/macrophages, dendritic cells, neutrophils, and mast cells. BTK inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. Besides their well-characterized role in inhibiting BCR signaling, BTKis also exert significant immunological influences outside the tumor cell that extend their therapeutic potential and impact on the immune system in different ways. This work elucidates the immunomodulatory mechanisms associated with BTK inhibition, focusing on CLL and other clinical contexts. We discuss how BTK inhibition affects various immune cells, including B cells, T cells, and macrophages. The effects of BTKis on the profiles of cytokines, also fundamental parts of the tumor microenvironment (TME), are summarized here as well. This review also appraises the implications of these immunomodulatory actions in the management of autoimmune diseases and infections. Summarizing the dual role of BTK inhibition in modulating malignant lymphocyte and immune cell functions, this paper highlights the broader potential clinical use of compounds targeting BTK.
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Affiliation(s)
- Qu Jiang
- Department for Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University Hospital of Leipzig, 04103 Leipzig, Germany; (Y.P.); (C.D.H.); (M.H.)
- Cancer Center Central Germany (CCCG), Leipzig-Jena, 04103 Leipzig, Germany
| | - Yayi Peng
- Department for Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University Hospital of Leipzig, 04103 Leipzig, Germany; (Y.P.); (C.D.H.); (M.H.)
- Cancer Center Central Germany (CCCG), Leipzig-Jena, 04103 Leipzig, Germany
| | - Carmen Diana Herling
- Department for Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University Hospital of Leipzig, 04103 Leipzig, Germany; (Y.P.); (C.D.H.); (M.H.)
- Cancer Center Central Germany (CCCG), Leipzig-Jena, 04103 Leipzig, Germany
| | - Marco Herling
- Department for Hematology, Cell Therapy, Hemostaseology, and Infectious Diseases, University Hospital of Leipzig, 04103 Leipzig, Germany; (Y.P.); (C.D.H.); (M.H.)
- Cancer Center Central Germany (CCCG), Leipzig-Jena, 04103 Leipzig, Germany
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Mehra S, Nicholls M, Taylor J. The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas. Int J Mol Sci 2024; 25:7516. [PMID: 39062757 PMCID: PMC11276629 DOI: 10.3390/ijms25147516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK's non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK's dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments.
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Affiliation(s)
- Shefali Mehra
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
| | - Miah Nicholls
- College of Arts and Sciences, University of Miami, Coral Gables, FL 33146, USA;
| | - Justin Taylor
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
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9
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Zeng X, Chen Q, Chen T. Nanomaterial-assisted oncolytic bacteria in solid tumor diagnosis and therapeutics. Bioeng Transl Med 2024; 9:e10672. [PMID: 39036084 PMCID: PMC11256190 DOI: 10.1002/btm2.10672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/29/2024] [Accepted: 04/08/2024] [Indexed: 07/23/2024] Open
Abstract
Cancer presents a formidable challenge in modern medicine due to the intratumoral heterogeneity and the dynamic microenvironmental niche. Natural or genetically engineered oncolytic bacteria have always been hailed by scientists for their intrinsic tumor-targeting and oncolytic capacities. However, the immunogenicity and low toxicity inevitably constrain their application in clinical practice. When nanomaterials, characterized by distinctive physicochemical properties, are integrated with oncolytic bacteria, they achieve mutually complementary advantages and construct efficient and safe nanobiohybrids. In this review, we initially analyze the merits and drawbacks of conventional tumor therapeutic approaches, followed by a detailed examination of the precise oncolysis mechanisms employed by oncolytic bacteria. Subsequently, we focus on harnessing nanomaterial-assisted oncolytic bacteria (NAOB) to augment the effectiveness of tumor therapy and utilizing them as nanotheranostic agents for imaging-guided tumor treatment. Finally, by summarizing and analyzing the current deficiencies of NAOB, this review provides some innovative directions for developing nanobiohybrids, intending to infuse novel research concepts into the realm of solid tumor therapy.
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Affiliation(s)
- Xiangdi Zeng
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- The First Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Qi Chen
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Tingtao Chen
- Department of Obstetrics and GynecologyThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- National Engineering Research Center for Bioengineering Drugs and the TechnologiesInstitute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
- School of PharmacyJiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
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10
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Kawata K, Hatano S, Baba A, Imabayashi K, Baba Y. Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice. Front Immunol 2024; 15:1388947. [PMID: 38638439 PMCID: PMC11024364 DOI: 10.3389/fimmu.2024.1388947] [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: 02/20/2024] [Accepted: 03/21/2024] [Indexed: 04/20/2024] Open
Abstract
Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.
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Affiliation(s)
| | | | | | | | - Yoshihiro Baba
- Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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11
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Parker J, Marten SM, Ó Corcora TC, Rajkov J, Dubin A, Roth O. The effects of primary and secondary bacterial exposure on the seahorse (Hippocampus erectus) immune response. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 153:105136. [PMID: 38185263 DOI: 10.1016/j.dci.2024.105136] [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: 10/24/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024]
Abstract
Evolutionary adaptations in the Syngnathidae teleost family (seahorses, pipefish and seadragons) culminated in an array of spectacular morphologies, key immune gene losses, and the enigmatic male pregnancy. In seahorses, genome modifications associated with immunoglobulins, complement, and major histocompatibility complex (MHC II) pathway components raise questions concerning their immunological efficiency and the evolution of compensatory measures that may act in their place. In this investigation heat-killed bacteria (Vibrio aestuarianus and Tenacibaculum maritimum) were used in a two-phased experiment to assess the immune response dynamics of Hippocampus erectus. Gill transcriptomes from double and single-exposed individuals were analysed in order to determine the differentially expressed genes contributing to immune system responses towards immune priming. Double-exposed individuals exhibited a greater adaptive immune response when compared with single-exposed individuals, while single-exposed individuals, particularly with V. aestuarianus replicates, associated more with the innate branch of the immune system. T. maritimum double-exposed replicates exhibited the strongest immune reaction, likely due to their immunological naivety towards the bacterium, while there are also potential signs of innate trained immunity. MHC II upregulated expression was identified in selected V. aestuarianus-exposed seahorses, in the absence of other pathway constituents suggesting a possible alternative or non-classical MHC II immune function in seahorses. Gene Ontology (GO) enrichment analysis highlighted prominent angiogenesis activity following secondary exposure, which could be linked to an adaptive immune process in seahorses. This investigation highlights the prominent role of T-cell mediated adaptive immune responses in seahorses when exposed to sequential foreign bacteria exposures. If classical MHC II pathway function has been lost, innate trained immunity in syngnathids could be a potential compensatory mechanism.
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Affiliation(s)
- Jamie Parker
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany.
| | - Silke-Mareike Marten
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
| | - Tadhg C Ó Corcora
- Marine Evolutionary Ecology, GEOMAR Helmholtz Centre for Ocean Research Kiel, D-24105, Kiel, Germany
| | - Jelena Rajkov
- Marine Evolutionary Ecology, GEOMAR Helmholtz Centre for Ocean Research Kiel, D-24105, Kiel, Germany
| | - Arseny Dubin
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
| | - Olivia Roth
- Marine Evolutionary Biology, Christian-Albrechts-University, D-24118, Kiel, Germany
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12
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Reid W, Romberg N. Inborn Errors of Immunity and Cytokine Storm Syndromes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:185-207. [PMID: 39117816 DOI: 10.1007/978-3-031-59815-9_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted.
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Affiliation(s)
- Whitney Reid
- Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Neil Romberg
- Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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13
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Fan X, Lu P, Cui XH, Wu P, Lin WR, Zhang D, Yuan SZ, Liu B, Chen FY, You H, Wei HD, He FC, Jia JD, Jiang Y. Repopulating Kupffer cells originate directly from hematopoietic stem cells. Stem Cell Res Ther 2023; 14:351. [PMID: 38072929 PMCID: PMC10712046 DOI: 10.1186/s13287-023-03569-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Kupffer cells (KCs) originate from yolk-sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at a steady state and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adults remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. METHODS We first traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models, respectively. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC-depletion in mice. Finally, we traced the fate of hematopoietic stem cells (HSCs) in an HSC-specific fate-mapping mouse model, in the context of chronic liver inflammation induced by repeated carbon tetrachloride treatment. RESULTS By using fate-mapping mouse models, we found no evidence that repopulating KCs originate from preexisting KCs or MOs and found that in response to KC-depletion, HSCs proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Then, in the chronic liver inflammation context, we confirmed that repopulating KCs originated directly from HSCs. CONCLUSION Taken together, these findings provided in vivo fate-mapping evidence that repopulating KCs originate directly from HSCs, which presents a completely novel understanding of the cellular origin of repopulating KCs and shedding light on the divergent roles of KCs in liver homeostasis and diseases.
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Affiliation(s)
- Xu Fan
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Pei Lu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Xiang-Hua Cui
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Peng Wu
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Wei-Ran Lin
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Dong Zhang
- Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, 10050, China
| | - Shong-Zong Yuan
- Department of Lymphoma, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China
| | - Bing Liu
- State Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China
| | - Fang-Yan Chen
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, 100050, China
| | - Han-Dong Wei
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Fu-Chu He
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, 102206, China.
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Diseases, Beijing, 100050, China.
| | - Ying Jiang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
- Anhui Medical University, Hefei, 230032, China.
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14
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Pérez-Torres I, Aisa-Álvarez A, Casarez-Alvarado S, Borrayo G, Márquez-Velasco R, Guarner-Lans V, Manzano-Pech L, Cruz-Soto R, Gonzalez-Marcos O, Fuentevilla-Álvarez G, Gamboa R, Saucedo-Orozco H, Franco-Granillo J, Soto ME. Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects. Int J Mol Sci 2023; 24:16610. [PMID: 38068931 PMCID: PMC10706209 DOI: 10.3390/ijms242316610] [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: 10/10/2023] [Revised: 11/14/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3- and NO2-), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.
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Affiliation(s)
- Israel Pérez-Torres
- Cardiovascular Biomedicine Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (I.P.-T.); (L.M.-P.)
| | - Alfredo Aisa-Álvarez
- Critical Care Department, American British Cowdray (ABC) Medical Center, PAI ABC Sur 136 No. 116, Col. las Américas, Mexico City 01120, Mexico; (A.A.-Á.); (O.G.-M.); (J.F.-G.)
| | - Sergio Casarez-Alvarado
- Immunology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (S.C.-A.); (R.M.-V.); (R.C.-S.)
| | - Gabriela Borrayo
- Instituto Mexicano del Seguro Social, Dirección de Prestaciones Médicas Coordinación de Innovación en Salud, Ciudad de México 06700, Mexico;
| | - Ricardo Márquez-Velasco
- Immunology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (S.C.-A.); (R.M.-V.); (R.C.-S.)
| | - Verónica Guarner-Lans
- Physiology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (V.G.-L.); (G.F.-Á.); (R.G.)
| | - Linaloe Manzano-Pech
- Cardiovascular Biomedicine Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (I.P.-T.); (L.M.-P.)
| | - Randall Cruz-Soto
- Immunology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (S.C.-A.); (R.M.-V.); (R.C.-S.)
| | - Omar Gonzalez-Marcos
- Critical Care Department, American British Cowdray (ABC) Medical Center, PAI ABC Sur 136 No. 116, Col. las Américas, Mexico City 01120, Mexico; (A.A.-Á.); (O.G.-M.); (J.F.-G.)
| | - Giovanny Fuentevilla-Álvarez
- Physiology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (V.G.-L.); (G.F.-Á.); (R.G.)
| | - Ricardo Gamboa
- Physiology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (V.G.-L.); (G.F.-Á.); (R.G.)
| | | | - Juvenal Franco-Granillo
- Critical Care Department, American British Cowdray (ABC) Medical Center, PAI ABC Sur 136 No. 116, Col. las Américas, Mexico City 01120, Mexico; (A.A.-Á.); (O.G.-M.); (J.F.-G.)
| | - María Elena Soto
- Immunology Department, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico; (S.C.-A.); (R.M.-V.); (R.C.-S.)
- Research Direction Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Mexico City 14380, Mexico
- Cardiovascular Line in American British Cowdray (ABC) Medical Center, PAI ABC Sur 136 No. 116, Col. Las Américas, Mexico City 01120, Mexico
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15
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Devarajan P, Vong AM, Castonguay CH, Silverstein NJ, Kugler-Umana O, Bautista BL, Kelly KA, Luban J, Swain SL. Cytotoxic CD4 development requires CD4 effectors to concurrently recognize local antigen and encounter type I IFN-induced IL-15. Cell Rep 2023; 42:113182. [PMID: 37776519 PMCID: PMC10842051 DOI: 10.1016/j.celrep.2023.113182] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 07/30/2023] [Accepted: 09/13/2023] [Indexed: 10/02/2023] Open
Abstract
Cytotoxic CD4 T cell effectors (ThCTLs) kill virus-infected major histocompatibility complex (MHC) class II+ cells, contributing to viral clearance. We identify key factors by which influenza A virus infection drives non-cytotoxic CD4 effectors to differentiate into lung tissue-resident ThCTL effectors. We find that CD4 effectors must again recognize cognate antigen on antigen-presenting cells (APCs) within the lungs. Both dendritic cells and B cells are sufficient as APCs, but CD28 co-stimulation is not needed. Optimal generation of ThCTLs requires signals induced by the ongoing infection independent of antigen presentation. Infection-elicited type I interferon (IFN) induces interleukin-15 (IL-15), which, in turn, supports CD4 effector differentiation into ThCTLs. We suggest that these multiple spatial, temporal, and cellular requirements prevent excessive lung ThCTL responses when virus is already cleared but ensure their development when infection persists. This supports a model where continuing infection drives the development of multiple, more differentiated subsets of CD4 effectors by distinct pathways.
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Affiliation(s)
| | - Allen M Vong
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Catherine H Castonguay
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Noah J Silverstein
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Olivia Kugler-Umana
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Bianca L Bautista
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Karen A Kelly
- Department of Animal Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jeremy Luban
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Susan L Swain
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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16
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Qian K, Fu S, Wang J, Li Y, Xian J, Ye J. Major histocompatibility complex class IIα and IIβ of pufferfish (Takifugu obscurus): Identification and functional characterization in response to bacterial challenge. JOURNAL OF FISH DISEASES 2023; 46:1049-1064. [PMID: 37357462 DOI: 10.1111/jfd.13824] [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: 03/25/2023] [Revised: 05/31/2023] [Accepted: 06/05/2023] [Indexed: 06/27/2023]
Abstract
Classical major histocompatibility complex (MHC) class II molecules play an essential role in immune system. In this study, MHC IIα (Pf-MHC IIα) and MHC IIβ (Pf-MHC IIβ) homology genes from pufferfish (Takifugu obscurus) were cloned and their functional characterization in response to bacterial challenge was identified. The nucleotide sequences of the open reading frames (ORFs) of pufferfish Pf-MHC IIα and Pf-MHC IIβ were 708 bp and 750 bp, encoding 235 aa and 249 aa, respectively. The structure of Pf-MHC IIα or Pf-MHC IIβ contained a signal peptide, an α1/β1 domain, an α2/β2 domain, a transmembrane region and a cytoplasmic region. Multiple sequence alignment and phylogenetic analysis showed that Pf-MHC IIα and Pf-MHC IIβ molecules had the highest similarity with Fugu rubripes (Takifugu rubripes). Cellular localization analysis indicated that the distribution of Pf-MHC IIα and Pf-MHC IIβ was in the lymphocyte membrane and cytoplasm. qRT-PCR results showed that Pf-MHC IIα and Pf-MHC IIβ expressed relatively high in skin, gills and gut. In addition, after stimulation challenge in vitro (lipopolysaccharide, or polyinosinic: polycytidylic acid) and in vivo (A. hydrophila), the mRNA expressions of Pf-MHC IIα and Pf-MHC IIβ were significantly up-regulated in lymphocytes and in tissues of skin, gills, gut and head kidney. Moreover, Pf-MHC IIα or Pf-MHC IIβ neutralization reduced the ability of A. hydrophila to induce the expressions of lymphocyte cytokines (TNF-α, IL-1β and IL-10). Overall, it is speculated that Pf-MHC IIα and Pf-MHC IIβ may play an important role in the host response against A. hydrophila in pufferfish.
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Affiliation(s)
- Kun Qian
- Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Shengli Fu
- Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Junru Wang
- Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Yuan Li
- Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, China
| | - Jianan Xian
- Hainan Provincial Key Laboratory for Functional Components Research and Utilization of Marine Bio-resources, Institute of Tropical Biosciences and Biotechnology, CATAS, Haikou, China
| | - Jianmin Ye
- Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, School of Life Sciences, South China Normal University, Guangzhou, China
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17
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Chen Y, Li S, Huang X, Wang C, Pan Y, Xiang Q, Feng Z, Fei L, Wu Y, Ruan Z, An Y, Chen Y. Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation. Mol Immunol 2023; 160:121-132. [PMID: 37429063 DOI: 10.1016/j.molimm.2023.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/18/2023] [Accepted: 07/02/2023] [Indexed: 07/12/2023]
Abstract
Our previous research demonstrated that the tetraspan MS4A6D is an adapter of VSIG4 that controls NLRP3 inflammasome activation (Sci Adv. 2019: eaau7426); however, the expression, distribution and biofunction of MS4A6D are still poorly understood. Here, we showed that MS4A6D is restricted to mononuclear phagocytes and that its gene transcript is controlled by the transcription factor NK2 homeobox-1 (NKX2-1). Ms4a6d-deficient (Ms4a6d-/-) mice showed normal macrophage development but manifested a greater survival advantage against endotoxin (lipopolysaccharide) challenge. Mechanistically, MS4A6D homodimers crosslinked with MHC class II antigen (MHC-II) to form a surface signaling complex under acute inflammatory conditions. MHC-II occupancy triggered Tyr241 phosphorylation in MS4A6D, leading to activation of SYK-CREB signaling cascades, further resulting in augmenting the transcription of proinflammatory genes (Il1b, Il6 and Tnfa) and amplifying the secretion of mitochondrial reactive oxygen species (mtROS). Deletion of Tyr241 or interruption of Cys237-mediated MS4A6D homodimerization in macrophages alleviated inflammation. Importantly, both Ms4a6dC237G and Ms4a6dY241G mutation mice phenocopied Ms4a6d-/- animals to prevent endotoxin lethality, highlighting MS4A6D as a novel target for treating macrophage-associated disorders.
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Affiliation(s)
- Yue Chen
- Institute of Medicine, Southwest University, Chongqing 400033, China
| | - Sirui Li
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Xiaoyong Huang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Chenhui Wang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China; Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
| | - Yue Pan
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Qun Xiang
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China; Chongqing International Institute for Immunology, Chongqing 400026, China
| | - Zeqing Feng
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China; Chongqing International Institute for Immunology, Chongqing 400026, China
| | - Lei Fei
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China
| | - Zhihua Ruan
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Yunfei An
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
| | - Yongwen Chen
- Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, China.
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18
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Duan X, Hu M, Yang L, Zhang S, Wang B, Li T, Tan Y, Li Y, Liu X, Zhan Z. IRG1 prevents excessive inflammatory responses and cardiac dysfunction after myocardial injury. Biochem Pharmacol 2023; 213:115614. [PMID: 37209857 DOI: 10.1016/j.bcp.2023.115614] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Acute myocardial infarction (MI) and chemotherapeutic drug administration can induce myocardial damage and cardiomyocyte cell death, and trigger the release of damage-associated molecular patterns (DAMPs) that initiate the aseptic inflammatory response. The moderate inflammatory response is beneficial for repairing damaged myocardium, while an excessive inflammatory response exacerbates myocardial injury, promotes scar formation, and results in a poor prognosis of cardiac diseases. Immune responsive gene 1 (IRG1) is specifically highly expressed in activated macrophages and mediates the production of tricarboxylic acid (TCA) cycle metabolite itaconate. However, the role of IRG1 in the inflammation and myocardial injury of cardiac stress-related diseases remains unknown. Here, we found that IRG1 knockout mice exhibited increased cardiac tissue inflammation and infarct size, aggravated myocardial fibrosis, and impaired cardiac function after MI and in vivo doxorubicin (Dox) administration. Mechanically, IRG1 deficiency enhanced the production of IL-6 and IL-1β by suppressing the nuclear factor red lineage 2-related factor 2 (NRF2) and activating transcription factor 3 (ATF3) pathway in cardiac macrophages. Importantly, 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, reversed the inhibited expression of NRF2 and ATF3 caused by IRG1 deficiency. Moreover, in vivo 4-OI administration inhibited the cardiac inflammation and fibrosis, and prevented adverse ventricle remodeling in IRG1 knockout mice with MI or Dox-induced myocardial injury. Our study uncovers the critical protective role of IRG1 in suppressing inflammation and preventing cardiac dysfunction under ischemic or toxic injury conditions, providing a potential target for the treatment of myocardial injury.
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Affiliation(s)
- Xuewen Duan
- Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200081, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Meiling Hu
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Linshan Yang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Sheng Zhang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Bo Wang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Tong Li
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yong Tan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yingke Li
- Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xingguang Liu
- Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China.
| | - Zhenzhen Zhan
- Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200081, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
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19
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Park J, Wu Y, Li Q, Choi J, Ju H, Cai Y, Lee J, Oh YK. Nanomaterials for antigen-specific immune tolerance therapy. Drug Deliv Transl Res 2023; 13:1859-1881. [PMID: 36094655 DOI: 10.1007/s13346-022-01233-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/26/2022]
Abstract
Impairment of immune tolerance might cause autologous tissue damage or overactive immune response against non-pathogenic molecules. Although autoimmune disease and allergy have complicated pathologies, the current strategies have mainly focused on symptom amelioration or systemic immunosuppression which can lead to fatal adverse events. The induction of antigen-specific immune tolerance may provide therapeutic benefits to autoimmune disease and allergic response, while reducing nonspecific immune adverse responses. Diverse nanomaterials have been studied to induce antigen-specific immune tolerance therapy. This review will cover the immunological background of antigen-specific tolerance, clinical importance of antigen-specific immune tolerance, and nanomaterials designed for autoimmune and allergic diseases. As nanomaterials for modulating immune tolerances, lipid-based nanoparticles, polymeric nanoparticles, and biological carriers have been covered. Strategies to provide antigen-specific immune tolerance have been addressed. Finally, current challenges and perspectives of nanomaterials for antigen-specific immune tolerance therapy will be discussed.
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Affiliation(s)
- Jinwon Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yina Wu
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Qiaoyun Li
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jaehyun Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyemin Ju
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu Cai
- College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Jaiwoo Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yu-Kyoung Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
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20
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Zhang SY, Xu QP, Shi LN, Li SW, Wang WH, Wang QQ, Lu LX, Xiao H, Wang JH, Li FY, Liang YM, Gong ST, Peng HR, Zhang Z, Tang H. Soluble CD4 effectively prevents excessive TLR activation of resident macrophages in the onset of sepsis. Signal Transduct Target Ther 2023; 8:236. [PMID: 37332010 DOI: 10.1038/s41392-023-01438-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 03/08/2023] [Accepted: 03/28/2023] [Indexed: 06/20/2023] Open
Abstract
T lymphopenia, occurring in the early phase of sepsis in response to systemic inflammation, is commonly associated with morbidity and mortality of septic infections. We have previously shown that a sufficient number of T cells is required to constrain Toll-like receptors (TLRs) mediated hyperinflammation. However, the underlying mechanisms remains unsolved. Herein, we unveil that CD4+ T cells engage with MHC II of macrophages to downregulate TLR pro-inflammatory signaling. We show further that the direct contact between CD4 molecule of CD4+ T cells or the ectodomain of CD4 (soluble CD4, sCD4), and MHC II of resident macrophages is necessary and sufficient to prevent TLR4 overactivation in LPS and cecal ligation puncture (CLP) sepsis. sCD4 serum concentrations increase after the onset of LPS sepsis, suggesting its compensatory inhibitive effects on hyperinflammation. sCD4 engagement enables the cytoplasmic domain of MHC II to recruit and activate STING and SHP2, which inhibits IRAK1/Erk and TRAF6/NF-κB activation required for TLR4 inflammation. Furthermore, sCD4 subverts pro-inflammatory plasma membrane anchorage of TLR4 by disruption of MHC II-TLR4 raft domains that promotes MHC II endocytosis. Finally, sCD4/MHCII reversal signaling specifically interferes with TLR4 but not TNFR hyperinflammation, and independent of the inhibitive signaling of CD40 ligand of CD4+ cells on macrophages. Therefore, a sufficient amount of soluble CD4 protein can prevent excessive inflammatory activation of macrophages via alternation of MHC II-TLR signaling complex, that might benefit for a new paradigm of preventive treatment of sepsis.
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Affiliation(s)
- Sheng-Yuan Zhang
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
- The Third People's Hospital of Shenzhen, Shenzhen, 518112, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Qiu-Ping Xu
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Li-Na Shi
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
- University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Shih-Wen Li
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Wei-Hong Wang
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Qing-Qing Wang
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Liao-Xun Lu
- The Laboratory of Genetic Regulators in The Immune System, Xin-xiang Medical University, Xin-xiang, Henan Province, 453003, China
| | - Hui Xiao
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Jun-Hong Wang
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Feng-Ying Li
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China
| | - Yin-Ming Liang
- The Laboratory of Genetic Regulators in The Immune System, Xin-xiang Medical University, Xin-xiang, Henan Province, 453003, China
| | - Si-Tang Gong
- The Joint Center of Translational Medicine, Guangzhou Women and Children's Medical Center and Institut Pasteur of Shanghai, Guangzhou, 510623, China
| | - Hao-Ran Peng
- Department of Microbiology, Naval Medical University, Shanghai, 200433, China.
| | - Zheng Zhang
- The Third People's Hospital of Shenzhen, Shenzhen, 518112, China.
| | - Hong Tang
- CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 210031, China.
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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21
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Zhang Y, Gao Y, Ding Y, Jiang Y, Chen H, Zhan Z, Liu X. Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming. MedComm (Beijing) 2023; 4:e306. [PMID: 37313329 PMCID: PMC10258526 DOI: 10.1002/mco2.306] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 06/15/2023] Open
Abstract
Epigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage-mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB-3, the KAT2A-specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen-induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli-triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor-erythroid 2-related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2-mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.
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Affiliation(s)
- Yunkai Zhang
- Department of Pathogen BiologyNaval Medical UniversityShanghaiChina
- National Key Laboratory of Immunity & InflammationNaval Medical UniversityShanghaiChina
| | - Ying Gao
- Department of RheumatologyChanghai Hospital, Naval Medical UniversityShanghaiChina
- Key Laboratory of Arrhythmias of the Ministry of Education of ChinaShanghai East Hospital, Tongji University School of MedicineShanghaiChina
| | - Yingying Ding
- Department of Pathogen BiologyNaval Medical UniversityShanghaiChina
| | - Yuyu Jiang
- Department of Pathogen BiologyNaval Medical UniversityShanghaiChina
| | - Huiying Chen
- Department of Pathogen BiologyNaval Medical UniversityShanghaiChina
| | - Zhenzhen Zhan
- Key Laboratory of Arrhythmias of the Ministry of Education of ChinaShanghai East Hospital, Tongji University School of MedicineShanghaiChina
- Department of Liver Surgery, Shanghai Institute of TransplantationRenji Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xingguang Liu
- Department of Pathogen BiologyNaval Medical UniversityShanghaiChina
- National Key Laboratory of Immunity & InflammationNaval Medical UniversityShanghaiChina
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22
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Zhang Y, Gao Y, Jiang Y, Ding Y, Chen H, Xiang Y, Zhan Z, Liu X. Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell Death Differ 2023; 30:1279-1292. [PMID: 36914768 PMCID: PMC10154333 DOI: 10.1038/s41418-023-01136-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 03/16/2023] Open
Abstract
Macrophages play a critical role in the immune homeostasis and host defense against invading pathogens. However, uncontrolled activation of inflammatory macrophages leads to tissue injury and even fuels autoimmunity. Hence the molecular mechanisms underlying macrophage activation need to be further elucidated. The effects of epigenetic modifications on the function of immune cells draw increasing attention. Here, we demonstrated that lysine-specific demethylase 5B (KDM5B), a classical transcriptional repressor in stem cell development and cancer, was required for the full activation of NF-κB signaling cascade and pro-inflammatory cytokine production in macrophages. KDM5B deficiency or inhibitor treatment protected mice from immunologic injury in both collagen-induced arthritis (CIA) model and endotoxin shock model. Genome-wide analysis of KDM5B-binding peaks identified that KDM5B was selectively recruited to the promoter of Nfkbia, the gene encoding IκBα, in activated macrophages. KDM5B mediated the H3K4me3 modification erasing and decreased chromatin accessibility of Nfkbia gene locus, coordinating the elaborate suppression of IκBα expression and the enhanced NF-κB-mediated macrophage activation. Our finding identifies the indispensable role of KDM5B in macrophage-mediated inflammatory responses and provides a candidate therapeutic target for autoimmune and inflammatory disorders.
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Affiliation(s)
- Yunkai Zhang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
- National Key Laboratory of Medical Immunology, Naval Medical University, Shanghai, 200433, China
| | - Ying Gao
- Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yuyu Jiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Yingying Ding
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Huiying Chen
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Yan Xiang
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China
| | - Zhenzhen Zhan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Liver Surgery, Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Xingguang Liu
- Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China.
- National Key Laboratory of Medical Immunology, Naval Medical University, Shanghai, 200433, China.
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23
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Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol 2023; 19:289-304. [PMID: 37055617 PMCID: PMC10100639 DOI: 10.1038/s41582-023-00800-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 04/15/2023]
Abstract
Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.
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Affiliation(s)
- Julia Krämer
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
| | - Amit Bar-Or
- Center for Neuroinflammation and Neurotherapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
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24
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Salim F, Gunawan H, Suwarsa O, Sutedja E. Increased Expression of Toll-Like Receptor (TLR) 2 and TLR6 on Peripheral Blood Monocytes by Induction of Staphylococcal Enterotoxin B During Exacerbation of Atopic Dermatitis Patients. Clin Cosmet Investig Dermatol 2023; 16:301-307. [PMID: 36748066 PMCID: PMC9899008 DOI: 10.2147/ccid.s401815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 01/24/2023] [Indexed: 02/01/2023]
Abstract
Background Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease that can be triggered by various precipitating factors, including colonization by Staphylococcus aureus (S. aureus). The toll-like receptor (TLR), which belongs to the family of pattern recognition receptors (PRR), can recognize components of S. aureus, such as staphylococcal enterotoxin B (SEB). This receptor is known to be expressed on monocytes. However, the understanding of the role of SEB in the pathogenesis of AD through the TLR pathway, especially TLR2 and TLR6, is not widely known. Purpose To investigate the expression of TLR2 and TLR6 on peripheral blood monocytes induced by SEB during AD exacerbations. Patients and Methods Twenty AD patients and 20 healthy subjects as a control group were selected. A 5 mL blood sample from each subject was taken for monocyte culture, which was induced by SEB for three days, and the outcomes were assessed by flow cytometry to evaluate TLR2 and TLR6 expression. Results The expression of TLR2 on peripheral blood monocytes in AD patients was increased compared to healthy controls (p = 0.000), but not for the expression of TLR6 (p = 0.304). In the AD group, TLR2 and TLR6 expression on peripheral blood monocytes after being induced by SEB was significantly increased compared to before induction (p = 0.025 and p = 0.023, respectively), but not in the control group (p = 0.737 and p = 0.100, respectively). Conclusion There is significantly increased expression of TLR2 and TLR6 on peripheral blood monocytes induced by SEB during exacerbation in AD patients.
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Affiliation(s)
- Fitria Salim
- Doctoral Study Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
- Department of Dermatology and Venereology, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
| | - Hendra Gunawan
- Department of Dermatology and Venereology, Faculty of Medicine, Universitas Padjadjaran–Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Oki Suwarsa
- Department of Dermatology and Venereology, Faculty of Medicine, Universitas Padjadjaran–Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
| | - Endang Sutedja
- Department of Dermatology and Venereology, Faculty of Medicine, Universitas Padjadjaran–Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
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25
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Charlesworth CT, Hsu I, Wilkinson AC, Nakauchi H. Immunological barriers to haematopoietic stem cell gene therapy. Nat Rev Immunol 2022; 22:719-733. [PMID: 35301483 PMCID: PMC8929255 DOI: 10.1038/s41577-022-00698-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 12/12/2022]
Abstract
Cell and gene therapies using haematopoietic stem cells (HSCs) epitomize the transformative potential of regenerative medicine. Recent clinical successes for gene therapies involving autologous HSC transplantation (HSCT) demonstrate the potential of genetic engineering in this stem cell type for curing disease. With recent advances in CRISPR gene-editing technologies, methodologies for the ex vivo expansion of HSCs and non-genotoxic conditioning protocols, the range of clinical indications for HSC-based gene therapies is expected to significantly expand. However, substantial immunological challenges need to be overcome. These include pre-existing immunity to gene-therapy reagents, immune responses to neoantigens introduced into HSCs by genetic engineering, and unique challenges associated with next-generation and off-the-shelf HSC products. By synthesizing these factors in this Review, we hope to encourage more research to address the immunological issues associated with current and next-generation HSC-based gene therapies to help realize the full potential of this field.
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Affiliation(s)
- Carsten T Charlesworth
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ian Hsu
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Adam C Wilkinson
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
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26
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Liu S, Li C, Yan W, Jin S, Wang K, Wang C, Gong H, Wu H, Fu X, Deng L, Lei C, He M, Wang H, Cheng Y, Wang Q, Lin S, Huang Y, Li D, Yang X. Using Blood Transcriptome Analysis to Determine the Changes in Immunity and Metabolism of Giant Pandas with Age. Vet Sci 2022; 9:vetsci9120667. [PMID: 36548828 PMCID: PMC9784451 DOI: 10.3390/vetsci9120667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/18/2022] [Accepted: 11/25/2022] [Indexed: 12/05/2022] Open
Abstract
A low reproductive rate coupled with human activities has endangered the giant panda, a species endemic to southwest China. Although giant pandas feed almost exclusively on bamboo, they retain carnivorous traits and suffer from carnivorous diseases. Additionally, their immune system is susceptible to aging, resulting in a reduced ability to respond to diseases. This study aimed to determine the genes and pathways expressed differentially with age in blood tissues. The differentially expressed genes in different age groups of giant pandas were identified by RNA-seq. The elderly giant pandas had many differentially expressed genes compared with the young group (3 years old), including 548 upregulated genes and 401 downregulated genes. Further, functional enrichment revealed that innate immune upregulation and adaptive immune downregulation were observed in the elderly giant pandas compared with the young giant pandas. Meanwhile, the immune genes in the elderly giant pandas changed considerably, including genes involved in innate immunity and adaptive immunity such as PLSCR1, CLEC7A, CCL5, CCR9, and EPAS1. Time series analysis found that giant pandas store glycogen by prioritizing fat metabolism at age 11, verifying changes in the immune system. The results reported in this study will provide a foundation for further research on disease prevention and the energy metabolism of giant pandas.
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Affiliation(s)
- Song Liu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Caiwu Li
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Wenjun Yan
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Senlong Jin
- Sichuan Wolong National Nature Reserve Administration, Wenchuan 623006, China
| | - Kailu Wang
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Chengdong Wang
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Huiling Gong
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Honglin Wu
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Xue Fu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Linhua Deng
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Changwei Lei
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Ming He
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Hongning Wang
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
| | - Yanxi Cheng
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Qian Wang
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Shanshan Lin
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Yan Huang
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
| | - Desheng Li
- China Conservation and Research Center for the Giant Panda, Key Laboratory of State Forestry and Grassland Administration on Conservation Biology of Rare Animals in the Giant Panda National Park, Chengdu 610083, China
- Correspondence: (D.L.); (X.Y.)
| | - Xin Yang
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610017, China
- Correspondence: (D.L.); (X.Y.)
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Li Z, Hadlich F, Wimmers K, Murani E. Glucocorticoid receptor hypersensitivity enhances inflammatory signaling and inhibits cell cycle progression in porcine PBMCs. Front Immunol 2022; 13:976454. [PMID: 36505401 PMCID: PMC9730246 DOI: 10.3389/fimmu.2022.976454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/10/2022] [Indexed: 11/27/2022] Open
Abstract
The consequences of glucocorticoid receptor (GR) hypersensitivity during infection have so far received little attention. We previously discovered that a natural gain-of-function Ala610Val substitution in the porcine GR aggravates response of pigs to lipopolysaccharide (LPS)-induced endotoxemia, which can be alleviated by dexamethasone (DEX) pretreatment. In this work, we investigated the relevant molecular basis of these phenotypes by transcriptomic profiling of porcine peripheral blood mononuclear cells (PBMCs) carrying different GR genotypes, in unstimulated conditions or in response to DEX and/or LPS in vitro. The Val allele differentially regulated abunda+nt genes in an additive-genetic manner. A subset of more than 200 genes was consistently affected by the substitution across treatments. This was associated with upregulation of genes related i.a. to endo-lysosomal system, lipid and protein catabolism, and immune terms including platelet activation, and antigen presentation, while downregulated genes were mainly involved in cell cycle regulation. Most importantly, the set of genes constitutively upregulated by Val includes members of the TLR4/LPS signaling pathway, such as LY96. Consequently, when exposing PBMCs to LPS treatment, the Val variant upregulated a panel of additional genes related to TLR4 and several other pattern recognition receptors, as well as cell death and lymphocyte signaling, ultimately amplifying the inflammatory responses. In contrast, when stimulated by DEX treatment, the Val allele orchestrated several genes involved in anti-inflammatory responses during infection. This study provides novel insights into the impact of GR hypersensitivity on the fate and function of immune cells, which may be useful for endotoxemia therapy.
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Affiliation(s)
- Zhiwei Li
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Frieder Hadlich
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Klaus Wimmers
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany,Faculty of Agricultural and Environmental Sciences, University Rostock, Rostock, Germany
| | - Eduard Murani
- Institute of Genome Biology, Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany,*Correspondence: Eduard Murani,
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28
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Cao T, Wang Z, Zhu X. The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System. J Inflamm Res 2022; 15:6427-6438. [PMID: 36452053 PMCID: PMC9704002 DOI: 10.2147/jir.s389958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/15/2022] [Indexed: 02/22/2025] Open
Abstract
Bruton's tyrosine kinase (BTK) is a central signaling node in B cells. BTK inhibition has witnessed great success in the treatment of B-cell malignancies. Additionally, in the immune system, BTK is also a prominent component linking a wide variety of immune-related pathways. Therefore, more and more studies attempting to dissect the role of BTK in autoimmune and inflammation progression have emerged in recent years. In particular, BTK expression was also found to be elevated within the central nervous system (CNS) during neuroinflammation. BTK inhibitors are capable of crossing the blood-brain barrier rapidly to modulate B cell functions, attenuate microglial activities and affect NLRP3 inflammasome pathways within the CNS to improve the outcome of diseases. Thus, BTK inhibition appears to be a promising approach to modulate dysregulated inflammation in the CNS and alleviate destruction caused by excessive inflammatory responses. This review will summarize the immunomodulatory mechanisms in which BTK is involved in the development of neurological diseases and discuss the therapeutic potential of BTK inhibition for the treatment of neuroinflammatory pathology.
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Affiliation(s)
- Tingyu Cao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Zengguang Wang
- Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Xiaodong Zhu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
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Wang N, Wang M, Jeevaratnam S, Rosenberg C, Ikezu TC, Shue F, Doss SV, Alnobani A, Martens YA, Wren M, Asmann YW, Zhang B, Bu G, Liu CC. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination. Mol Neurodegener 2022; 17:75. [PMID: 36419137 PMCID: PMC9682675 DOI: 10.1186/s13024-022-00577-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 10/21/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear. METHODS To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination. RESULTS We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice. CONCLUSIONS Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.
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Affiliation(s)
- Na Wang
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Minghui Wang
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
| | - Suren Jeevaratnam
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Cassandra Rosenberg
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Tadafumi C. Ikezu
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Francis Shue
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Sydney V. Doss
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Alla Alnobani
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Yuka A. Martens
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Melissa Wren
- grid.417467.70000 0004 0443 9942Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Yan W. Asmann
- grid.417467.70000 0004 0443 9942Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Bin Zhang
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
| | - Guojun Bu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
| | - Chia-Chen Liu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
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Jin YP, Nevarez-Mejia J, Terry AQ, Sosa RA, Heidt S, Valenzuela NM, Rozengurt E, Reed EF. Cross-Talk between HLA Class I and TLR4 Mediates P-Selectin Surface Expression and Monocyte Capture to Human Endothelial Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1359-1369. [PMID: 36165200 PMCID: PMC9635437 DOI: 10.4049/jimmunol.2200284] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/22/2022] [Indexed: 11/19/2022]
Abstract
Donor-specific HLA Abs contribute to Ab-mediated rejection (AMR) by binding to HLA molecules on endothelial cells (ECs) and triggering intracellular signaling, leading to EC activation and leukocyte recruitment. The molecular mechanisms involving donor-specific HLA Ab-mediated EC activation and leukocyte recruitment remain incompletely understood. In this study, we determined whether TLRs act as coreceptors for HLA class I (HLA I) in ECs. We found that human aortic ECs express TLR3, TLR4, TLR6, and TLR10, but only TLR4 was detected on the EC surface. Consequently, we performed coimmunoprecipitation experiments to examine complex formation between HLA I and TLR4. Stimulation of human ECs with HLA Ab increased the amount of complex formation between HLA I and TLR4. Reciprocal coimmunoprecipitation with a TLR4 Ab confirmed that the crosslinking of HLA I increased complex formation between TLR4 and HLA I. Knockdown of TLR4 or MyD88 with small interfering RNAs inhibited HLA I Ab-stimulated P-selectin expression, von Willebrand factor release, and monocyte recruitment on ECs. Our results show that TLR4 is a novel coreceptor for HLA I to stimulate monocyte recruitment on activated ECs. Taken together with our previous published results, we propose that HLA I molecules form two separate signaling complexes at the EC surface, that is, with TLR4 to upregulate P-selectin surface expression and capture of monocytes to human ECs and integrin β4 to induce mTOR-dependent firm monocyte adhesion via ICAM-1 clustering on ECs, two processes implicated in Ab-mediated rejection.
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Affiliation(s)
- Yi-Ping Jin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Allyson Q Terry
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Rebecca A Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands; and
| | - Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA;
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Arthur R, Wathen A, Lemm EA, Stevenson FK, Forconi F, Linley AJ, Steele AJ, Packham G, Valle-Argos B. BTK-independent regulation of calcium signalling downstream of the B-cell receptor in malignant B-cells. Cell Signal 2022; 96:110358. [PMID: 35597428 DOI: 10.1016/j.cellsig.2022.110358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 11/20/2022]
Abstract
BTK inhibitors (BTKi) have dramatically improved outcomes for patients with chronic lymphocytic leukaemia (CLL) and some forms of B-cell lymphoma. However, new strategies are needed to enhance responses. Here we have performed a detailed analysis of the effects of BTKi on B-cell receptor (BCR)-induced signalling using primary malignant cells from CLL patients and B-lymphoma cell lines. Although BTK is considered as a key activator of PLCγ2, BTKi (ibrutinib and acalabrutinib) failed to fully inhibit calcium responses in CLL samples with strong BCR signalling capacity. This BTKi-resistant calcium signalling was sufficient to engage downstream calcium-dependent transcription and suppress CLL cell apoptosis and was entirely independent of BTK and not just its kinase activity as similar results were obtained using a BTK-degrading PROTAC. BTK-independent calcium signalling was also observed in two B-lymphoma cell lines where BTKi had little effect on the initial phase of the calcium response but did accelerate the subsequent decline in intracellular calcium. In contrast to BTKi, calcium responses were completely blocked by inhibition of SYK in CLL and lymphoma cells. Engagement of BTK-independent calcium responses was associated with BTK-independent phosphorylation of PLCγ2 on Y753 and Y759 in both CLL and lymphoma cells. Moreover, in CLL samples, inhibition of RAC, which can mediate BTK-independent activation of PLCγ2, cooperated with ibrutinib to suppress calcium responses. BTK-independent calcium signalling may limit the effectiveness of BTKi to suppress BCR signalling responses and our results suggest inhibition of SYK or dual inhibition of BTK and RAC as alternative strategies to strengthen pathway blockade.
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Affiliation(s)
- Rachael Arthur
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Alexander Wathen
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Elizabeth A Lemm
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Freda K Stevenson
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Francesco Forconi
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Adam J Linley
- Department of Molecular Physiology and Cell Signalling, University of Liverpool, Institute of Systems, Molecular and Integrative Biology, 5(th) Floor Nuffield Building, Crown Street, Liverpool L69 3BX, United Kingdom
| | - Andrew J Steele
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
| | - Graham Packham
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
| | - Beatriz Valle-Argos
- Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom
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Nguyen TP, Nguyen BT, Nan FH, Lee MC, Lee PT. TLR23, a fish-specific TLR, recruits MyD88 and TRIF to activate expression of a range of effectors in melanomacrophages in Nile tilapia (Oreochromis niloticus). FISH & SHELLFISH IMMUNOLOGY 2022; 126:34-46. [PMID: 35598740 DOI: 10.1016/j.fsi.2022.05.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
Nile tilapia (Oreochromis niloticus) is an important food fish species that is mainly cultivated in tropical and subtropical countries. However, microbial diseases have created various difficulties for this industry. The fundamental prerequisite for tackling disease outbreak prevention and disease resistance is to know how hosts' immune responses against invading microbes are initiated. Toll-like receptors (TLRs) are vital pattern recognition receptors and play pivotal roles in the cellular innate immunity defense that is able to recognize pathogen-associated molecular patterns (PAMPs). In this study, Oreochromis niloticus TLR23 (OnTLR23) was cloned and bioinformatic analyses revealed that OnTLR23 is not an ortholog of mammalian TLR13 as previously suggested. The basal transcript level of OnTLR23 was found to be higher in the immune-related organs and was upregulated in the spleen and/or head kidney following Aeromonas hydrophila, Streptococcus agalactiae or poly I:C injections, and increased in the melanomacrophage-like tilapia head kidney (THK) cell line after LPS and zymosan stimulation. Furthermore, we demonstrated for the first time that OnTLR23 locates mainly in the intracellular region in fish cells and the constitutively active form of OnTLR23 promotes the expression of molecules related to antigen presentation, proinflammatory cytokines, antimicrobial peptides and type I interferon in THK cells. A co-immunoprecipitation assay revealed that OnTLR23 can interact with both OnMyD88 and OnTRIF, but not with OnTIRAP. A luciferase assay showed that the NF-κB activity was not elevated in the OnTLR23 overexpressed THK cells after treatment with ligand for TLR13 as well as other known purified bacterial-derived ligands of TLRs. Taken together, OnTLR23 is likely to recruit OnMyD88 and OnTRIF as adaptors to induce the expression of various effectors in melanomacrophages, but its corresponding ligand is an issue awaiting further investigation.
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Affiliation(s)
- Tan Phat Nguyen
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan
| | - Bao Trung Nguyen
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan; College of Aquaculture and Fisheries, Can Tho University, Viet Nam
| | - Fan-Hua Nan
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan; Center of Excellence for Ocean Engineering, National Taiwan Ocean University, Keelung City, 20224, Taiwan
| | - Meng-Chou Lee
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan; Center of Excellence for Ocean Engineering, National Taiwan Ocean University, Keelung City, 20224, Taiwan; Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung City, 20224, Taiwan
| | - Po-Tsang Lee
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan.
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Hathaway‐Schrader JD, Novince CM. GPR65, a novel regulator of helper T-cell polarization in inflammatory bowel disease. Clin Transl Med 2022; 12:e857. [PMID: 35678010 PMCID: PMC9178348 DOI: 10.1002/ctm2.857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/20/2022] [Accepted: 04/18/2022] [Indexed: 11/11/2022] Open
Affiliation(s)
- Jessica D. Hathaway‐Schrader
- Department of Oral Health Sciences, College of Dental MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Pediatrics‐Division of Endocrinology, College of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Stomatology‐Division of Periodontics, College of Dental Medicine, Medical University of South CarolinaMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Chad M. Novince
- Department of Oral Health Sciences, College of Dental MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Pediatrics‐Division of Endocrinology, College of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Stomatology‐Division of Periodontics, College of Dental Medicine, Medical University of South CarolinaMedical University of South CarolinaCharlestonSouth CarolinaUSA
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Wang JC, Sun L. PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review. Int J Mol Sci 2022; 23:5837. [PMID: 35628647 PMCID: PMC9143160 DOI: 10.3390/ijms23105837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 11/23/2022] Open
Abstract
There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to Ph(-) MPN.
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Affiliation(s)
- Jen-Chin Wang
- Division of Hematology/Oncology, Brookdale University Hospital Medical Center, Brooklyn, NY 11212, USA;
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Qing-Qi R, Ya-Wen L, Huan C, Yu Z, Yun-Fei A, Xue-Mei T, Xiao-Dong Z, Zhi-Yong Z. Retrospective study of 98 patients with X-linked agammaglobulinemia complicated with arthritis. Clin Rheumatol 2022; 41:1889-1897. [PMID: 35171366 DOI: 10.1007/s10067-022-06095-1] [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: 08/12/2021] [Revised: 01/19/2022] [Accepted: 01/30/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE We preformed this retrospective study of clinical manifestation, imaging feature, and mutations to describe joint involvement in X-linked agammaglobulinemia (XLA) patients, aimed to provide recommendation for physicians. METHODS A total number of 98 XLA patients who have been diagnosed between January 2000 and February 2020 were enrolled and grouped based on whether they developed arthritis and analyzed for the clinical, imaging, and gene mutation data using the t test or the Mann-Whitney test. RESULTS Forty-five out of 98 patients (45.9%) had joint involvement, 40.8% had symptom prior to the diagnosis of XLA, and 54.1% had no articular symptom. Patients with joint involvement had a higher median diagnostic age of XLA and initial IgG level than patients without it, while their intravenous immunoglobulin was lower (p < 0.05). Knee, hip, and ankle were the most frequent joint, and oligoarthritis (≦ 4 joints) was more common than polyarthritis (88.9% vs 11.1%). Red and tenderness were the most frequent clinical symptoms (80%) with 24.4% reporting limited activity and 8.9% reporting deformity. Imaging data collected from 32 patients indicated that joint effusion (53.3%), synovitis (15.5%), and swollen soft tissue (15.5%) were the most common feature. Seventeen patients were treated by antibiotics plus intravenous immunoglobulin (IVIG) with an effective rate of 70.6%, and 28 patients only received IVIG with an effective rate of 67.9%. In comparison to patients without arthritis who have higher frequency nonsense and frameshift mutation, patients with arthritis had a higher incidence of missense mutation (p < 0.05). CONCLUSION High prevalence of arthritis among X-linked agammaglobulinemia patients and subsequent progression through IVIG replacement therapy highlight the importance of timely diagnosis and better management of these patients. Our finding indicated a potential correlation between genotype and phenotype, and further research on the mechanism of arthritis in XLA patients could increase physicians' awareness and improve patients' prognosis. Key Points • This study described the feature of arthritis in XLA patients and indicated a potential correlation between this complication and genotype.
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Affiliation(s)
- Ran Qing-Qi
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Li Ya-Wen
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Chen Huan
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Zhang Yu
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - An Yun-Fei
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - Tang Xue-Mei
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - Zhao Xiao-Dong
- National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China.,The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Zhang Zhi-Yong
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
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Tan Y, Li T, Hu M, Wang B, Zhou Q, Jiang Y, Zhang S, Duan X, Yang J, Liu X, Zhan Z. PHLPP1 deficiency ameliorates cardiomyocyte death and cardiac dysfunction through inhibiting Mcl-1 degradation. Cell Signal 2022; 92:110281. [DOI: 10.1016/j.cellsig.2022.110281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/25/2022] [Accepted: 02/07/2022] [Indexed: 12/31/2022]
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Hathaway-Schrader JD, Aartun JD, Poulides NA, Kuhn MB, McCormick BE, Chew ME, Huang E, Darveau RP, Westwater C, Novince CM. Commensal oral microbiota induces osteoimmunomodulatory effects separate from systemic microbiome in mice. JCI Insight 2022; 7:140738. [PMID: 35077397 PMCID: PMC8876522 DOI: 10.1172/jci.insight.140738] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 01/19/2022] [Indexed: 11/17/2022] Open
Abstract
Commensal microbes critically regulate skeletal homeostasis, yet the impact of specific microbiota communities on osteoimmune response mechanisms is unknown. To discern osteoimmunomodulatory effects imparted by the commensal oral microbiota that are distinct from the systemic microbiota, osteoimmunology studies were performed in both alveolar bone and nonoral skeletal sites of specific pathogen–free (SPF) versus germ-free (GF) mice and SPF mice subjected to saline versus chlorhexidine oral rinses. SPF versus GF mice had reduced cortical/trabecular bone and an enhanced pro-osteoclastic phenotype in alveolar bone. TLR signaling and Th17 cells that have known pro-osteoclastic actions were increased in alveolar BM, but not long BM, of SPF versus GF mice. MHC II antigen presentation genes and activated DCs and CD4+ T cells were elevated in alveolar BM, but not long BM, of SPF versus GF mice. These findings were substantiated by in vitro allostimulation studies demonstrating increased activated DCs derived from alveolar BM, but not long BM, of SPF versus GF mice. Chlorhexidine antiseptic rinse depleted the oral, but not gut, bacteriome in SPF mice. Findings from saline- versus chlorhexidine-treated SPF mice corroborated outcomes from SPF versus GF mice, which reveals that the commensal oral microbiota imparts osteoimmunomodulatory effects separate from the systemic microbiome.
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Affiliation(s)
- Jessica D. Hathaway-Schrader
- Department of Oral Health Sciences, College of Dental Medicine
- Department of Pediatrics-Division of Endocrinology, College of Medicine, and
- Department of Stomatology-Division of Periodontics, College of Dental Medicine, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | | | | | - Megan B. Kuhn
- Department of Oral Health Sciences, College of Dental Medicine
| | | | - Michael E. Chew
- Department of Oral Health Sciences, College of Dental Medicine
| | - Emily Huang
- Department of Oral Health Sciences, College of Dental Medicine
| | - Richard P. Darveau
- Department of Periodontics, School of Dentistry, and
- Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, Washington, USA
| | - Caroline Westwater
- Department of Oral Health Sciences, College of Dental Medicine
- Department of Microbiology and Immunology, Hollings Cancer Center, MUSC, Charleston, South Carolina, USA
| | - Chad M. Novince
- Department of Oral Health Sciences, College of Dental Medicine
- Department of Pediatrics-Division of Endocrinology, College of Medicine, and
- Department of Stomatology-Division of Periodontics, College of Dental Medicine, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
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Megale ÂAA, Magnoli FC, Guidolin FR, Godoi KS, Portaro FCV, Dias-da-Silva W. Bitis arietans Snake Venom and Kn-Ba, a Snake Venom Serine Protease, Induce the Production of Inflammatory Mediators in THP-1 Macrophages. Toxins (Basel) 2021; 13:toxins13120906. [PMID: 34941743 PMCID: PMC8705107 DOI: 10.3390/toxins13120906] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 11/16/2022] Open
Abstract
Bitis arietans is a snake of medical importance found throughout sub-Saharan Africa and in savannas and pastures of Morocco and western Arabia. The effects of its venom are characterized by local and systemic alterations, such as inflammation and cardiovascular and hemostatic disturbances, which can lead to victims' death or permanent disability. To better characterize the inflammatory process induced by this snake's venom, the participation of eicosanoids and PAF (platelet- activating factor) in this response were demonstrated in a previous study. In addition, edema and early increased vascular permeability followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity were accompanied by the production of the eicosanoids LTB4, LTC4, TXB2, and PGE2, and local and systemic production of IL-6 and MCP-1. In this context, the present study focused on the identification of inflammatory mediators produced by human macrophages derived from THP-1 cells in response to Bitis arietans venom (BaV), and Kn-Ba, a serine protease purified from this venom. Here, we show that Kn-Ba, and even the less intensive BaV, induced the production of the cytokine TNF and the chemokines RANTES and IL-8. Only Kn-Ba was able to induce the production of IL-6, MCP-1, and IP-10, whereas PGE2 was produced only in response to BaV. Finally, the release of IL-1β in culture supernatants suggests the activation of the inflammasomes by the venom of Bitis arietans and by Kn-Ba, which will be investigated in more detail in future studies.
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Affiliation(s)
- Ângela Alice Amadeu Megale
- Immunochemistry Laboratory, Butantan Institute, São Paulo 05503-900, Brazil; (F.C.M.); (F.R.G.); (K.S.G.)
- Correspondence: (Â.A.A.M.); (F.C.V.P.); (W.D.-d.-S.)
| | - Fabio Carlos Magnoli
- Immunochemistry Laboratory, Butantan Institute, São Paulo 05503-900, Brazil; (F.C.M.); (F.R.G.); (K.S.G.)
| | - Felipe Raimondi Guidolin
- Immunochemistry Laboratory, Butantan Institute, São Paulo 05503-900, Brazil; (F.C.M.); (F.R.G.); (K.S.G.)
| | - Kemily Stephanie Godoi
- Immunochemistry Laboratory, Butantan Institute, São Paulo 05503-900, Brazil; (F.C.M.); (F.R.G.); (K.S.G.)
| | - Fernanda Calheta Vieira Portaro
- Laboratory of Structure and Function of Biomolecules, Butantan Institute, São Paulo 05503-900, Brazil
- Correspondence: (Â.A.A.M.); (F.C.V.P.); (W.D.-d.-S.)
| | - Wilmar Dias-da-Silva
- Immunochemistry Laboratory, Butantan Institute, São Paulo 05503-900, Brazil; (F.C.M.); (F.R.G.); (K.S.G.)
- Correspondence: (Â.A.A.M.); (F.C.V.P.); (W.D.-d.-S.)
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Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) in Innate Immunity. TLRs, NLRs, and RLRs Ligands as Immunotherapeutic Agents for Hematopoietic Diseases. Int J Mol Sci 2021; 22:ijms222413397. [PMID: 34948194 PMCID: PMC8704656 DOI: 10.3390/ijms222413397] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 02/07/2023] Open
Abstract
The innate immune system plays a pivotal role in the first line of host defense against infections and is equipped with patterns recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRRS, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) recognize distinct microbial components and directly activate immune cells. TLRs are transmembrane receptors, while NLRs and RLRs are intracellular molecules. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. The innate immune system also influences pathways involved in cancer immunosurveillance. Natural and synthetic agonists of TLRs, NLRs, or RLRs can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment, and are being explored as promising adjuvants in cancer immunotherapies. In this review, we provide a concise overview of TLRs, NLRs, and RLRs: their structure, functions, signaling pathways, and regulation. We also describe various ligands for these receptors and their possible application in treatment of hematopoietic diseases.
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Wilson KR, Jenika D, Blum AB, Macri C, Xu B, Liu H, Schriek P, Schienstock D, Francis L, Makota FV, Ishido S, Mueller SN, Lahoud MH, Caminschi I, Edgington-Mitchell LE, Villadangos JA, Mintern JD. MHC Class II Ubiquitination Regulates Dendritic Cell Function and Immunity. THE JOURNAL OF IMMUNOLOGY 2021; 207:2255-2264. [PMID: 34599081 DOI: 10.4049/jimmunol.2001426] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 08/17/2021] [Indexed: 11/19/2022]
Abstract
MHC class II (MHC II) Ag presentation by dendritic cells (DCs) is critical for CD4+ T cell immunity. Cell surface levels of MHC II loaded with peptide is controlled by ubiquitination. In this study, we have examined how MHC II ubiquitination impacts immunity using MHC IIKRKI/KI mice expressing mutant MHC II molecules that are unable to be ubiquitinated. Numbers of conventional DC (cDC) 1, cDC2 and plasmacytoid DCs were significantly reduced in MHC IIKRKI/KI spleen, with the remaining MHC IIKRKI/KI DCs expressing an altered surface phenotype. Whereas Ag uptake, endosomal pH, and cathepsin protease activity were unaltered, MHC IIKRKI/KI cDC1 produced increased inflammatory cytokines and possessed defects in Ag proteolysis. Immunization of MHC IIKRKI/KI mice identified impairments in MHC II and MHC class I presentation of soluble, cell-associated and/or DC-targeted OVA via mAb specific for DC surface receptor Clec9A (anti-Clec9A-OVA mAb). Reduced T cell responses and impaired CTL killing was observed in MHC IIKRKI/KI mice following immunization with cell-associated and anti-Clec9A-OVA. Immunization of MHC IIKRKI/KI mice failed to elicit follicular Th cell responses and generated barely detectable Ab to anti-Clec9A mAb-targeted Ag. In summary, MHC II ubiquitination in DCs impacts the homeostasis, phenotype, cytokine production, and Ag proteolysis by DCs with consequences for Ag presentation and T cell and Ab-mediated immunity.
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Affiliation(s)
- Kayla R Wilson
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Devi Jenika
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Annabelle B Blum
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Christophe Macri
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Bangyan Xu
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Haiyin Liu
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Patrick Schriek
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Dominik Schienstock
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
| | - Lauren Francis
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - F Victor Makota
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Satoshi Ishido
- Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Scott N Mueller
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
| | - Mireille H Lahoud
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Irina Caminschi
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia.,Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Laura E Edgington-Mitchell
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.,Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, Bluestone Center for Clinical Research, New York, NY; and.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Jose A Villadangos
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia; .,Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia
| | - Justine D Mintern
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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41
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Harikrishnan R, Devi G, Balasundaram C, Van Doan H, Jaturasitha S, Saravanan K, Ringø E. Impact of cinnamaldehyde on innate immunity and immune gene expression in Channa striatus against Aphanomyces invadans. FISH & SHELLFISH IMMUNOLOGY 2021; 117:1-16. [PMID: 34274424 DOI: 10.1016/j.fsi.2021.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 07/05/2021] [Accepted: 07/15/2021] [Indexed: 06/13/2023]
Abstract
The effect of cinnamaldehyde (CM) enriched diet on immunity and cytokine gene expression in Channa striatus against Aphanomyces invadans is reported. C. striatus was uniformly divided into eight groups (n = 25 fish each) and fed with formulated diets with 0, 5, 10, and 15 mg kg-1 CM enriched diet. In healthy and infected groups fed with 5 mg kg-1 diet the leukocytes count increased significantly after 4th week; with 10 mg kg-1 CM diet the increase manifested after 6th week, but with 15 mg kg-1 not even after 8th week. In both groups, 5 mg kg-1 CM diet resulted in a significant increase in the serum total protein, albumin, and globulin levels after 4th week, whereas with other diets this effect was observed only after 6th week. Similarly, with any enriched diet the lysozyme activity increased significantly, but with 15 mg kg-1 CM diet only after 6th week. In both groups the complement activity and lymphocyte production increased significantly when fed with 5 mg kg-1 CM diet after 4th week while with other enriched diets only after 6th week. The phagocytic activity increased significantly in both groups fed with 5 mg kg-1 CM diet after 6th week, whereas the SOD activity increased after 4th week. The IgM production increased significantly in both groups fed with 5 mg kg-1 CM diet after 2nd week, while with 5 and 10 mg kg-1 CM diet after 4th week. In both groups, the expression of CXCR3α was significant on 4th week when fed with 10 mg kg-1 CM diet, while in the healthy group fed with 15 mg kg-1 CM diet the expression manifested earlier than 4th week. However, when fed with 10 and 15 mg kg-1 CM diets the increase was observed on 6th week; whereas, the expression of MHC-I reached the maximum on 6th week with any enriched diet. The results indicate that in C. striatus the innate immunity and expression of cytokine and immune related genes were significantly modulated when fed with 5 mg kg-1 CM diet on 4th week against A. invadans.
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Affiliation(s)
- Ramasamy Harikrishnan
- Department of Zoology, Pachaiyappa's College for Men, Kanchipuram, 631 501, Tamil Nadu, India.
| | - Gunapathy Devi
- Department of Zoology, Nehru Memorial College, Puthanampatti, 621 007, Tamil Nadu, India
| | - Chellam Balasundaram
- Department of Herbal and Environmental Science, Tamil University, Thanjavur, 613 005, Tamil Nadu, India
| | - Hien Van Doan
- Department of Animal and Aquatic Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, 50200, Thailand; Science and Technology Research Institute, Chiang Mai University, 239 Huay Keaw Rd., Suthep, Muang, Chiang Mai, 50200, Thailand.
| | - Sanchai Jaturasitha
- Department of Animal and Aquatic Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, 50200, Thailand; Science and Technology Research Institute, Chiang Mai University, 239 Huay Keaw Rd., Suthep, Muang, Chiang Mai, 50200, Thailand
| | | | - Einar Ringø
- Norwegian College of Fishery Science, Faculty of Bioscience, Fisheries and Economics, UiT The Arctic University of Norway, Tromsø, Norway
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42
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Zhu S, Gokhale S, Jung J, Spirollari E, Tsai J, Arceo J, Wu BW, Victor E, Xie P. Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets - Beyond B Lymphocytes. Front Cell Dev Biol 2021; 9:727531. [PMID: 34485307 PMCID: PMC8414982 DOI: 10.3389/fcell.2021.727531] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/26/2021] [Indexed: 12/24/2022] Open
Abstract
The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.
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Affiliation(s)
- Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Jaeyong Jung
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Eris Spirollari
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Jemmie Tsai
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Johann Arceo
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Ben Wang Wu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Eton Victor
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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43
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Saikh KU, Ranji CM. Cells Stimulated with More Than One Toll-Like Receptor-Ligand in the Presence of a MyD88 Inhibitor Augmented Interferon- β via MyD88-Independent Signaling Pathway. Viral Immunol 2021; 34:646-652. [PMID: 34287077 DOI: 10.1089/vim.2021.0020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Host exposure to pathogens engage multiple pathogen recognition receptors (PRRs) including toll-like receptors (TLRs); recruit intracellular signaling adaptor proteins primarily myeloid differentiation primary response protein 88 (MyD88) for activating downstream signaling cascades, which culminate in the production of type I interferons (IFNs), proinflammatory cytokines, and chemokines; and impede pathogen replication and dissemination. However, recent studies highlight that absence of MyD88 increased antiviral type I IFN induction, and MyD88-/- mice showed a higher survival rate compared with the low survival rate of the MyD88+/+ mice, implicating MyD88 limits antiviral type I IFN response. As a single infectious agent may harbor multiple PRR agonists, which trigger different sets of TLR-initiated immune signaling, we examined whether MyD88 inhibition during stimulation of cells with more than one TLR-ligand would augment type I IFN. We stimulated human U87- and TLR3-transfected HEK293-TLR7 cells with TLR-ligands, such as lipopolysaccharides (LPS) (TLR4-ligand) plus poly I:C (TLR3-ligand) or imiquimod (R837, TLR7-ligand) plus poly I:C, in the presence of compound 4210, a previously reported MyD88 inhibitor, and measured IFN-β response using an enzyme-linked immunosorbent assay. Our results showed that when U87- or TLR3-transfected HEK293-TLR7 cells were stimulated with TLR-ligands, such as poly I:C plus LPS or poly I:C plus R837, IFN-β production was significantly increased with MyD88 inhibition in a dose-dependent manner. Collectively, these results indicate that during more than one TLR-ligand-induced immune signaling event, impairment of antiviral type I IFN response was restored by inhibition of MyD88 through MyD88-independent pathway of type I IFN signaling, thus, offer a MyD88-targeted approach for type I IFN induction.
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Affiliation(s)
- Kamal U Saikh
- Department of Bacteriology, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA
| | - Cyra M Ranji
- Department of Bacteriology, United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA
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44
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Guan D, Wang Z, Huo J, Xu S, Lam KP. Bruton's tyrosine kinase regulates gut immune homeostasis through attenuating Th1 response. Cell Death Dis 2021; 12:431. [PMID: 33931590 PMCID: PMC8087775 DOI: 10.1038/s41419-021-03702-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD) is driven by multiple genetic and environmental risk factors. Patients with mutations in Bruton’s tyrosine kinase (BTK) is known to manifest high prevalence of intestinal disorders including IBD. Although BTK mediates the signaling of various immune receptors, little is known how BTK maintains the homeostasis of the gut immune system. Here, we show that BTK-deficiency promotes IBD progression in a mouse model of colitis. Interestingly, the increased colitis susceptibility of BTK-deficient mice is not caused by gut microbiota changes but rather arises from enhanced pro-inflammatory Th1 response. More importantly, we find the heightened Th1 response in BTK-deficient mice to result from both T cell-extrinsic and -intrinsic mechanisms. BTK-deficient dendritic cells secret elevated levels of the Th1-polarizing cytokine IL-12 and BTK-deficient T cells are inherently more prone to Th1 differentiation. Thus, BTK plays critical roles in maintaining gut immune homeostasis and preventing inflammation via regulating T-cell polarization.
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Affiliation(s)
- Di Guan
- NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore.,Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Zixi Wang
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jianxin Huo
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Shengli Xu
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Kong-Peng Lam
- NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore. .,Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
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45
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Good L, Benner B, Carson WE. Bruton's tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment. Cancer Immunol Immunother 2021; 70:2439-2451. [PMID: 33818636 PMCID: PMC8019691 DOI: 10.1007/s00262-021-02908-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/02/2021] [Indexed: 12/15/2022]
Abstract
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. BTK has been shown to contribute to a variety of cellular pathways in myeloid cells including signaling in the NLRP3 inflammasome, receptor activation of nuclear factor-κβ and inflammation, chemokine receptor activation affecting migration, and phagocytosis. Myeloid cells are crucial components of the tumor microenvironment and suppressive myeloid cells contribute to cancer progression, highlighting a potential role for BTK inhibition in the treatment of malignancy. The increased interest in BTK inhibition in cancer has resulted in many preclinical studies that are testing the efficacy of using single-agent BTK inhibitors. Moreover, the ability of tumor cells to develop resistance to single-agent checkpoint inhibitors has resulted in clinical studies utilizing BTK inhibitors in combination with these agents to improve clinical responses. Furthermore, BTK regulates the immune response in microbial and viral infections through B cells and myeloid cells such as monocytes and macrophages. In this review, we describe the role that BTK plays in supporting suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), while also discussing the anticancer effects of BTK inhibition and briefly describe the role of BTK signaling and BTK inhibition in microbial and viral infections.
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Affiliation(s)
- Logan Good
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Brooke Benner
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - William E Carson
- Department of Surgery, Division of Surgical Oncology, Tzagournis Medical Research Facility, The Ohio State University, Columbus, OH, USA.
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46
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Saikh KU. MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity. Immunol Res 2021; 69:117-128. [PMID: 33834387 PMCID: PMC8031343 DOI: 10.1007/s12026-021-09188-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022]
Abstract
The continuous emergence of infectious pathogens along with antimicrobial resistance creates a need for an alternative approach to treat infectious diseases. Targeting host factor(s) which are critically involved in immune signaling pathways for modulation of host immunity offers to treat a broad range of infectious diseases. Upon pathogen-associated ligands binding to the Toll-like/ IL-1R family, and other cellular receptors, followed by recruitment of intracellular signaling adaptor proteins, primarily MyD88, trigger the innate immune responses. But activation of host innate immunity strongly depends on the correct function of MyD88 which is tightly regulated. Dysregulation of MyD88 may cause an imbalance that culminates to a wide range of inflammation-associated syndromes and diseases. Furthermore, recent reports also describe that MyD88 upregulation with many viral infections is linked to decreased antiviral type I IFN response, and MyD88-deficient mice showed an increase in survivability. These reports suggest that MyD88 is also negatively involved via MyD88-independent pathways of immune signaling for antiviral type I IFN response. Because of its expanding role in controlling host immune signaling pathways, MyD88 has been recognized as a potential drug target in a broader drug discovery paradigm. Targeting BB-loop of MyD88, small molecule inhibitors were designed by structure-based approach which by blocking TIR-TIR domain homo-dimerization have shown promising therapeutic efficacy in attenuating MyD88-mediated inflammatory impact, and increased antiviral type I IFN response in experimental mouse model of diseases. In this review, we highlight the reports on MyD88-linked immune response and MyD88-targeted therapeutic approach with underlying mechanisms for controlling inflammation and antiviral type I IFN response. HIGHLIGHTS: • Host innate immunity is activated upon PAMPs binding to PRRs followed by immune signaling through TIR domain-containing adaptor proteins mainly MyD88. • Structure-based approach led to develop small-molecule inhibitors which block TIR domain homodimerization of MyD88 and showed therapeutic efficacy in limiting severe inflammation-associated impact in mice. • Therapeutic intervention of MyD88 also showed an increase in antiviral effect with strong type I IFN signaling linked to increased phosphorylation of IRFs via MyD88-independent pathway. • MyD88 inhibitors might be potentially useful as a small-molecule therapeutics for modulation of host immunity against inflammatory diseases and antiviral therapy. • However, prior clinical use of more in-depth efforts should be focused for suitability of the approach in deploying to complex diseases including COPD and COVID-19 in limiting inflammation-associated syndrome to infection.
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Affiliation(s)
- Kamal U Saikh
- Department of Bacterial Immunology, Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD, 21702, USA.
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47
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Shi Y, Shi Q, Shen Q, Zhang Q, Cao X. Dicer-independent snRNA/snoRNA-derived nuclear RNA 3 regulates tumor-associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription. Cancer Commun (Lond) 2021; 41:140-153. [PMID: 33455092 PMCID: PMC7896748 DOI: 10.1002/cac2.12131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Small RNAs (sRNAs) extensively mediate gene-specific chromatin regulation in lower organisms. As a dominant type of functional sRNAs in mature mammals, microRNAs mainly regulate gene expression at post-transcription level in the cytoplasm. Currently, whether there exists a type of nuclear-localized sRNAs mediating gene-specific epigenetic regulation in mature mammalian cells remains largely unclear. Here, we profiled sRNAs enriched in the nucleus and investigated their function in mediating gene-specific epigenetic regulation in anti-tumor immunity. METHODS We established cytoplasmic and nuclear transcriptomes of sRNAs of dendritic cells (DCs) using high-throughput sequencing. Transcription abundances of sRNAs and mRNAs were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. The associations between sRNAs and Argonaute (AGO) proteins were detected by RNA immunoprecipitation analysis. Synthesized sRNAs and locked nucleic acid (LNA) -modified sRNA inhibitors were used to screen the function of sRNAs in innate immune cells. The effect of sRNA on the enrichment of either chromatin remodeler or histone modification at the gene promoter was analyzed by chromatin immunoprecipitation (ChIP)-qPCR assay. Chromatin accessibility qPCR assay was used to detect the accessibility of gene promoters. A B16 melanoma-bearing mouse model was established to determine the function of sRNAs in tumor-associated macrophages (TAMs) and their effect on tumor growth. RESULTS We identified a new class of nucleus-localized sRNAs, named snRNA/snoRNA-derived nuclear RNAs (sdnRNAs). Some sdnRNAs were Dicer-independent and had no association with Argonaute proteins. sdnRNA-3, the most abundant Dicer-independent sdnRNAs identified in our analysis, was selected as a representative to examine the biological function of sdnRNAs. sdnRNA-3 selectively inhibited the transcription of Nos2 in macrophages during innate immune response by repressing the chromatin accessibility at Nos2 gene promoter. sdnRNA-3 promoted the enrichments of repressive chromatin-remodeling regulator Mi-2β and the repressive histone modification H3K27me3 at Nos2 gene promoter. In the B16 melanoma mouse model, we found higher expression of sdnRNA-3 in M2 TAMs than M1 TAMs and DCs. Transfer of sdnRNA-3-silenced macrophages inhibited tumor growth with increased expression of inducible nitric oxide synthase (iNOS) in TAMs. CONCLUSIONS Our results demonstrated that the sdnRNA-3 repressed the transcription of Nos2 by repressing chromatin accessibility at the promoter, providing new insights into the regulation of macrophage function in tumor immunity.
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Affiliation(s)
- Yang Shi
- Institute of ImmunologyZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Qingzhu Shi
- Institute of ImmunologyZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Qicong Shen
- National Key Laboratory of Medical Immunology & Institute of ImmunologySecond Military Medical UniversityShanghai200433P. R. China
| | - Qian Zhang
- National Key Laboratory of Medical Immunology & Institute of ImmunologySecond Military Medical UniversityShanghai200433P. R. China
| | - Xuetao Cao
- Institute of ImmunologyZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
- National Key Laboratory of Medical Immunology & Institute of ImmunologySecond Military Medical UniversityShanghai200433P. R. China
- Department of ImmunologyInstitute of Basic Medical ResearchChinese Academy of Medical SciencesBeijing100005P. R. China
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48
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Huang L, Fang X, Zhang X, Wu W, Yao H, Fang Q. RON Expression Mediates Lipopolysaccharide-Mediated Dendritic Cell Maturation via March-I. Front Cell Infect Microbiol 2021; 10:606340. [PMID: 33537243 PMCID: PMC7848161 DOI: 10.3389/fcimb.2020.606340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/30/2020] [Indexed: 11/13/2022] Open
Abstract
The macrophage stimulating protein (MSP)-Recepteur d'origine nantais (RON) signaling pathway regulates macrophage function. Here, we verified RON receptor expression in bone marrow-derived dendritic cells (BMDCs) by real time-PCR, Western blot, and flow cytometry. Flow cytometry was used to detect the changes in MHC II and CD86 expression following the inhibition of RON in BMDCs and splenic dendritic cells (DCs). Immunoprecipitation and Western blot were used to detect the level of MHC II and CD86 ubiquitination. An enzyme-linked immunosorbent assay was used to detect cytokine release, and a mixed lymphocyte reaction was performed to evaluate DC maturity. The results show that the inhibition of RON leads to an increase in March-1 transcription, which intensifies the ubiquitination of MHC II and CD86 and ultimately leads to a decreased level of these two molecules. The mixed lymphocyte reaction provided evidence that RON inhibition decreased the ability of DCs to promote the proliferation of T cells. The MSP-RON signaling pathway may play an important role in lipopolysaccharide (LPS)-stimulated DC maturation through March-I and may protect DC differentiation following LPS stimulation.
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Affiliation(s)
- Lingtong Huang
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Xueling Fang
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Xuan Zhang
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Department of Infectious Disease, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Weifang Wu
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Hangping Yao
- State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Qiang Fang
- Department of Critical Care Units, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
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49
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Gradtke AC, Mentrup T, Lehmann CHK, Cabrera-Cabrera F, Desel C, Okakpu D, Assmann M, Dalpke A, Schaible UE, Dudziak D, Schröder B. Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2021; 206:164-180. [PMID: 33239420 DOI: 10.4049/jimmunol.2000151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 10/30/2020] [Indexed: 12/30/2022]
Abstract
Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1β, whereas production of IL-10 and IFN-β is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.
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Affiliation(s)
- Ann-Christine Gradtke
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Torben Mentrup
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Christian H K Lehmann
- Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, D-91052 Erlangen, Germany.,Medical Immunology Campus Erlangen, D-91054 Erlangen, Germany.,Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany.,Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg, D-91054 Erlangen, Germany
| | - Florencia Cabrera-Cabrera
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany.,Biochemical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany
| | - Christine Desel
- Biochemical Institute, Christian-Albrechts-University Kiel, D-24118 Kiel, Germany
| | - Darian Okakpu
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Maike Assmann
- Priority Program Infections, Division of Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, and German Center for Infection Research, partner site Borstel, D-23845 Borstel, Germany; and
| | - Alexander Dalpke
- Institute of Medical Microbiology and Hygiene, Technische Universität Dresden, D-01307 Dresden, Germany
| | - Ulrich E Schaible
- Priority Program Infections, Division of Cellular Microbiology, Research Center Borstel, Leibniz Lung Center, and German Center for Infection Research, partner site Borstel, D-23845 Borstel, Germany; and
| | - Diana Dudziak
- Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg, University Hospital Erlangen, D-91052 Erlangen, Germany.,Medical Immunology Campus Erlangen, D-91054 Erlangen, Germany.,Deutsches Zentrum Immuntherapie, D-91054 Erlangen, Germany.,Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg, D-91054 Erlangen, Germany
| | - Bernd Schröder
- Institute of Physiological Chemistry, Technische Universität Dresden, D-01307 Dresden, Germany;
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50
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Arana-Argáez VE, Ceballos-Góngora E, Alvarez-Sánchez ME, Euan-Canto A, Lara-Riegos J, Torres-Romero JC. In Vitro Activation of Macrophages by an MHC Class II-restricted Trichomonas Vaginalis TvZIP8-derived Synthetic Peptide. Immunol Invest 2020; 51:88-102. [DOI: 10.1080/08820139.2020.1810703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
| | - Emanuel Ceballos-Góngora
- Laboratorio De Farmacología, Facultad De Química, Universidad Autónoma De Yucatán, Mérida, México
- Laboratorio De Bioquímica Y Genética Molecular, Facultad De Química, Universidad Autónoma De Yucatán, Mérida, México
| | | | - Antonio Euan-Canto
- Laboratorio De Bioquímica Y Genética Molecular, Facultad De Química, Universidad Autónoma De Yucatán, Mérida, México
| | - Julio Lara-Riegos
- Laboratorio De Bioquímica Y Genética Molecular, Facultad De Química, Universidad Autónoma De Yucatán, Mérida, México
| | - Julio César Torres-Romero
- Laboratorio De Bioquímica Y Genética Molecular, Facultad De Química, Universidad Autónoma De Yucatán, Mérida, México
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