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Li S, Chen L, Wu T, Wu J, Yang H, Ju Q, Liu Z, Chen W, Zhang D, Hao Y. Cell Membrane-Coated Nanotherapeutics for the Targeted Treatment of Acute and Chronic Colitis. Biomater Res 2024; 28:0102. [PMID: 39512421 PMCID: PMC11542430 DOI: 10.34133/bmr.0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/28/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024] Open
Abstract
Integrin α4β1 and α4β7 are overexpressed in macrophages and leukocytes and play important roles in mediating cell homing and recruitment to inflammatory tissues. Herein, to enhance the targeting ability of nanotherapeutics for inflammatory bowel disease (IBD) treatment, cyclosporine A-loaded nanoparticles (CsA NPs) were coated with macrophage membranes (MM-CsA NPs) or leukocyte membranes (LM-CsA NPs). In vitro experiments demonstrated that the physicochemical properties of the nanotherapeutics (e.g., size, zeta potential, polymer dispersity index, and drug release profiles) did not obviously change after cell membrane coating. However, integrin α4β1 and α4β7 were expressed in MM-CsA NPs and LM-CsA NPs, respectively, which significantly inhibited normal macrophage phagocytosis and obviously increased uptake by proinflammatory macrophages and endothelial cells. In vivo experiments verified that cell membrane-coated nanotherapeutics have longer retention times in inflammatory intestinal tissues. Importantly, LM-CsA NPs significantly mitigated weight loss, alleviated colon shortening, decreased disease activity indices (DAIs), and promoted colon tissue repair in acute and chronic colitis model mice. Furthermore, LM-CsA NPs significantly decreased the expression of inflammatory factors such as TNF-α and IL-6 and increased the expression of gut barrier-related proteins such as E-cadherin, ZO-1, and occludin protein in colitis mice.
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Affiliation(s)
- Shan Li
- Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Army Medical University (Third Military Medical University), Shigatse, Tibet Autonomous Region 857000, China
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Lei Chen
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Tianyu Wu
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Jingfeng Wu
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Hong Yang
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Qian Ju
- Department of Urology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Zhicheng Liu
- Department of Urology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Wensheng Chen
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Dinglin Zhang
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Yingxue Hao
- Department of Vascular Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
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Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, Sheppard D, Sundaram AB. IL-13 and IL-17A activate β1 integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle. Proc Natl Acad Sci U S A 2024; 121:e2401251121. [PMID: 39136993 PMCID: PMC11348015 DOI: 10.1073/pnas.2401251121] [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: 01/19/2024] [Accepted: 07/14/2024] [Indexed: 08/15/2024] Open
Abstract
Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of β1 integrins detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease-relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the β1-activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide β1-CHAMP that forces an extended-open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine-induced activation of β1 integrins is regulated by a common pathway of NF-κB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2 at focal adhesions, resulting in β1 integrin activation. Taken together, these data identify a pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant β1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.
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Affiliation(s)
- Uyen Ngo
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA94143
- Sandler Asthma Basic Research Center, University of California, San Francisco, CA94143
| | - Ying Shi
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA94143
| | - Prescott Woodruff
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA94143
- Sandler Asthma Basic Research Center, University of California, San Francisco, CA94143
| | - Kevan Shokat
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA94143
- Howard Hughes Medical Institute, University of California, San Francisco, CA94143
| | - William DeGrado
- Cardiovascular Research Institute, University of California, San Francisco, CA94143
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA94143
| | - Hyunil Jo
- Cardiovascular Research Institute, University of California, San Francisco, CA94143
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA94143
| | - Dean Sheppard
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA94143
- Cardiovascular Research Institute, University of California, San Francisco, CA94143
| | - Aparna B. Sundaram
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, CA94143
- Sandler Asthma Basic Research Center, University of California, San Francisco, CA94143
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Wang Z, Xu J, Mo L, Zhan R, Zhang J, Liu L, Jiang J, Zhang Y, Bai Y. The Application Potential of the Regulation of Tregs Function by Irisin in the Prevention and Treatment of Immune-Related Diseases. Drug Des Devel Ther 2024; 18:3005-3023. [PMID: 39050796 PMCID: PMC11268596 DOI: 10.2147/dddt.s465713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Irisin is a muscle factor induced by exercise, generated through the proteolytic cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC-5). Numerous studies have shown that irisin plays a significant role in regulating glucose and lipid metabolism, inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. Additionally, irisin can exert immunomodulatory functions by regulating regulatory T cells (Tregs). Tregs are a highly differentiated subset of mature T cells that play a key role in maintaining self-immune homeostasis and are closely related to infections, inflammation, immune-related diseases, and tumors. Irisin exerts persistent positive effects on Treg cell functions through various mechanisms, including regulating Treg cell differentiation and proliferation, improving their function, modulating the balance of immune cells, increasing the production of anti-inflammatory cytokines, and enhancing metabolic functions, thereby helping to maintain immune homeostasis and prevent immune-related diseases. As an important myokine, irisin interacts with receptors on the cell membrane, activating multiple intracellular signaling pathways to regulate cell metabolism, proliferation, and function. Although the specific receptor for irisin has not been fully identified, integrins are considered potential receptors. Irisin activates various signaling pathways, including AMPK, MAPK, and PI3K/Akt, through integrin receptors, thereby exerting multiple biological effects. These research findings provide important clues for understanding the mechanisms of irisin's action and theoretical basis for its potential applications in metabolic diseases and immunomodulation. This article reviews the relationship between irisin and Tregs, as well as the research progress of irisin in immune-related diseases such as multiple sclerosis, myasthenia gravis, acquired immune deficiency syndrome, type 1 diabetes, sepsis, and rheumatoid arthritis. Studies have revealed that irisin plays an important role in immune regulation by improving the function of Tregs, suggesting its potential application value in the treatment of immune-related diseases.
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Affiliation(s)
- Zhengjiang Wang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jiaqi Xu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Liqun Mo
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Renshu Zhan
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yingying Zhang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yiping Bai
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
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4
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Zhang J, Yao Z. Immune cell trafficking: a novel perspective on the gut-skin axis. Inflamm Regen 2024; 44:21. [PMID: 38654394 DOI: 10.1186/s41232-024-00334-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
Immune cell trafficking, an essential mechanism for maintaining immunological homeostasis and mounting effective responses to infections, operates under a stringent regulatory framework. Recent advances have shed light on the perturbation of cell migration patterns, highlighting how such disturbances can propagate inflammatory diseases from their origin to distal organs. This review collates and discusses current evidence that demonstrates atypical communication between the gut and skin, which are conventionally viewed as distinct immunological spheres, in the milieu of inflammation. We focus on the aberrant, reciprocal translocation of immune cells along the gut-skin axis as a pivotal factor linking intestinal and dermatological inflammatory conditions. Recognizing that the translation of these findings into clinical practices is nascent, we suggest that therapeutic strategies aimed at modulating the axis may offer substantial benefits in mitigating the widespread impact of inflammatory diseases.
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Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Liu Z, Zhou J, Wu S, Chen Z, Wu S, Chen L, Zhu X, Li Z. Why Treg should be the focus of cancer immunotherapy: The latest thought. Biomed Pharmacother 2023; 168:115142. [PMID: 37806087 DOI: 10.1016/j.biopha.2023.115142] [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: 04/08/2023] [Revised: 06/26/2023] [Accepted: 07/07/2023] [Indexed: 10/10/2023] Open
Abstract
Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in the immune system. What's more, regulatory T cells often play an immunosuppressive role, which mainly plays a role in maintaining the stability of the immune system and regulating the immune response in the body. However, recent studies have shown that not only playing a role in autoimmune diseases, organ transplantation, and other aspects, regulatory T cells can also play a role in the immune escape of tumors in the body, through various mechanisms to help tumor cells escape from the demic immune system, weakening the anti-cancer effect in the body. For a better understanding of the role that regulatory T cells can play in cancer, and to be able to use regulatory T cells for tumor immunotherapy more quickly. This review focuses on the research progress of various mechanisms of regulatory T cells in the tumor environment, the related research of tumor cells acting on regulatory T cells, and the existing various therapeutic methods acting on regulatory T cells.
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Affiliation(s)
- Ziyu Liu
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Jiajun Zhou
- Kidney Department, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Shihui Wu
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Zhihong Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Shuhong Wu
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Ling Chen
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Xiao Zhu
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China; Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China.
| | - Zesong Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.
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6
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Shahgoli VK, Dubik M, Pilecki B, Skallerup S, Schmidt SG, Detlefsen S, Sorensen GL, Holmskov U, Baradaran B, Moeller JB. Expression of FIBCD1 by intestinal epithelial cells alleviates inflammation-driven tumorigenesis in a mouse model of colorectal cancer. Front Oncol 2023; 13:1280891. [PMID: 38090485 PMCID: PMC10715588 DOI: 10.3389/fonc.2023.1280891] [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: 08/21/2023] [Accepted: 11/06/2023] [Indexed: 01/05/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers. METHODS In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression. RESULTS Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis. CONCLUSION Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.
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Affiliation(s)
- Vahid Khaze Shahgoli
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Magdalena Dubik
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Bartosz Pilecki
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Sofie Skallerup
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Sandra Gaedt Schmidt
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Grith L. Sorensen
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Uffe Holmskov
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jesper B. Moeller
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
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Sun H, Lee HS, Kim SHJ, Fernandes de Lima M, Gingras AR, Du Q, McLaughlin W, Ablack J, Lopez-Ramirez MA, Lagarrigue F, Fan Z, Chang JT, VanDyke D, Spangler JB, Ginsberg MH. IL-2 can signal via chemokine receptors to promote regulatory T cells' suppressive function. Cell Rep 2023; 42:112996. [PMID: 37598341 PMCID: PMC10564087 DOI: 10.1016/j.celrep.2023.112996] [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: 09/07/2022] [Revised: 04/18/2023] [Accepted: 08/02/2023] [Indexed: 08/22/2023] Open
Abstract
Canonical interleukin-2 (IL-2) signaling via the high-affinity CD25-containing IL-2 receptor-Janus kinase (JAK)1,3-signal transducer and activator of transcription 5 (STAT5) pathway is essential for development and maintenance of CD4+CD25HiFoxp3+ regulatory T cells (Tregs) that support immune homeostasis. Here, we report that IL-2 signaling via an alternative CD25-chemokine receptor pathway promotes the suppressive function of Tregs. Using an antibody against CD25 that biases IL-2 signaling toward this alternative pathway, we establish that this pathway increases the suppressive activity of Tregs and ameliorates murine experimental autoimmune encephalomyelitis (EAE). Furthermore, heparan sulfate, an IL-2-binding element of cell surfaces and extracellular matrix, or an engineered IL-2 immunocytokine can also direct IL-2 signaling toward this alternative pathway. Overall, these data reveal a non-canonical mechanism for IL-2 signaling that promotes suppressive functions of Tregs, further elucidates how IL-2 supports immune homeostasis, and suggests approaches to promote or suppress Treg functions.
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Affiliation(s)
- Hao Sun
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Ho-Sup Lee
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Sarah Hyun-Ji Kim
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | | | | | - Qinyi Du
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Wilma McLaughlin
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Jailail Ablack
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Miguel A Lopez-Ramirez
- University of California San Diego School of Medicine, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, La Jolla, CA, USA
| | | | - Zhichao Fan
- University of Connecticut School of Medicine, Farmington, CT, USA
| | - John T Chang
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Derek VanDyke
- Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Jamie B Spangler
- Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Mark H Ginsberg
- University of California San Diego School of Medicine, La Jolla, CA, USA.
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Kamioka Y, Ueda Y, Kondo N, Tokuhiro K, Ikeda Y, Bergmeier W, Kinashi T. Distinct bidirectional regulation of LFA1 and α4β7 by Rap1 and integrin adaptors in T cells under shear flow. Cell Rep 2023; 42:112580. [PMID: 37267105 PMCID: PMC10592472 DOI: 10.1016/j.celrep.2023.112580] [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: 06/14/2022] [Revised: 04/04/2023] [Accepted: 05/16/2023] [Indexed: 06/04/2023] Open
Abstract
Bidirectional control of integrin activation plays crucial roles in cell adhesive behaviors, but how integrins are specifically regulated by inside-out and outside-in signaling has not been fully understood. Here, we report distinct bidirectional regulation of major lymphocyte homing receptors LFA1 and α4β7 in primary T cells. A small increase of Rap1 activation in L-selectin-mediated tether/rolling was boosted by the outside-in signaling from ICAM1-interacting LFA1 through subsecond, simultaneous activation of Rap1 GTPase and talin1, but not kindlin-3, resulting in increased capture and slowing. In contrast, none of them were required for tether/rolling by α4β7 on MAdCAM1. High Rap1 activation with chemokines or the loss of Rap1-inactivating proteins Rasa3 and Sipa1 increased talin1/kindlin-3-dependent arrest with high-affinity binding of LFA1 to membrane-anchored ICAM1. However, despite increased affinity of α4β7, activated Rap1 severely suppressed adhesion on MAdCAM1 under shear flow, indicating the critical importance of a sequential outside-in/inside-out signaling for α4β7.
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Affiliation(s)
- Yuji Kamioka
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Yoshihiro Ueda
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Naoyuki Kondo
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Keizo Tokuhiro
- Department of Genome Editing, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Yoshiki Ikeda
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Wolfgang Bergmeier
- Department of Biochemistry and Biophysics, Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tatsuo Kinashi
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
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9
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Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity 2023; 56:240-255. [PMID: 36792571 DOI: 10.1016/j.immuni.2023.01.004] [Citation(s) in RCA: 140] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 02/16/2023]
Abstract
Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
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Affiliation(s)
- Stanislav Dikiy
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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10
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Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation. Nat Rev Gastroenterol Hepatol 2023; 20:50-64. [PMID: 35945456 DOI: 10.1038/s41575-022-00663-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/07/2022] [Indexed: 12/27/2022]
Abstract
Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body's fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut-liver, gut-joint and gut-brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.
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11
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Torres-Gomez A, Fiyouzi T, Guerra-Espinosa C, Cardeñes B, Clares I, Toribio V, Reche PA, Cabañas C, Lafuente EM. Expression of the phagocytic receptors αMβ2 and αXβ2 is controlled by RIAM, VASP and Vinculin in neutrophil-differentiated HL-60 cells. Front Immunol 2022; 13:951280. [PMID: 36238292 PMCID: PMC9552961 DOI: 10.3389/fimmu.2022.951280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/23/2022] [Indexed: 11/29/2022] Open
Abstract
Activation of the integrin phagocytic receptors CR3 (αMβ2, CD11b/CD18) and CR4 (αXβ2, CD11c/CD18) requires Rap1 activation and RIAM function. RIAM controls integrin activation by recruiting Talin to β2 subunits, enabling the Talin-Vinculin interaction, which in term bridges integrins to the actin-cytoskeleton. RIAM also recruits VASP to phagocytic cups and facilitates VASP phosphorylation and function promoting particle internalization. Using a CRISPR-Cas9 knockout approach, we have analyzed the requirement for RIAM, VASP and Vinculin expression in neutrophilic-HL-60 cells. All knockout cells displayed abolished phagocytosis that was accompanied by a significant and specific reduction in ITGAM (αM), ITGAX (αX) and ITGB2 (β2) mRNA, as revealed by RT-qPCR. RIAM, VASP and Vinculin KOs presented reduced cellular F-actin content that correlated with αM expression, as treatment with the actin filament polymerizing and stabilizing drug jasplakinolide, partially restored αM expression. In general, the expression of αX was less responsive to jasplakinolide treatment than αM, indicating that regulatory mechanisms independent of F-actin content may be involved. The Serum Response Factor (SRF) was investigated as the potential transcription factor controlling αMβ2 expression, since its coactivator MRTF-A requires actin polymerization to induce transcription. Immunofluorescent MRTF-A localization in parental cells was primarily nuclear, while in knockouts it exhibited a diffuse cytoplasmic pattern. Localization of FHL-2 (SRF corepressor) was mainly sub-membranous in parental HL-60 cells, but in knockouts the localization was disperse in the cytoplasm and the nucleus, suggesting RIAM, VASP and Vinculin are required to maintain FHL-2 close to cytoplasmic membranes, reducing its nuclear localization and inhibiting its corepressor activity. Finally, reexpression of VASP in the VASP knockout resulted in a complete reversion of the phenotype, as knock-ins restored αM expression. Taken together, our results suggest that RIAM, VASP and Vinculin, are necessary for the correct expression of αMβ2 and αXβ2 during neutrophilic differentiation in the human promyelocytic HL-60 cell line, and strongly point to an involvement of these proteins in the acquisition of a phagocytic phenotype.
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Affiliation(s)
- Alvaro Torres-Gomez
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
- *Correspondence: Esther M. Lafuente, ; Alvaro Torres-Gomez,
| | - Tara Fiyouzi
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
| | - Claudia Guerra-Espinosa
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Beatriz Cardeñes
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
| | - Irene Clares
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
| | - Víctor Toribio
- Tissue and Organ Homeostasis Program (Cell-Cell Communication and Inflammation Unit), Centre for Molecular Biology "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Pedro A. Reche
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
| | - Carlos Cabañas
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
- Tissue and Organ Homeostasis Program (Cell-Cell Communication and Inflammation Unit), Centre for Molecular Biology "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Esther M. Lafuente
- Department of Immunology, Ophthalmology and Otorhinolaryngology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Inflammatory Diseases and Immune Disorders (Lymphocyte Immunobiology Unit), Madrid, Spain
- *Correspondence: Esther M. Lafuente, ; Alvaro Torres-Gomez,
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12
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Lee HS, Sun H, Lagarrigue F, Kim SHJ, Fox JW, Sherman NE, Gingras AR, Ginsberg MH. Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs. J Exp Med 2022; 219:e20211637. [PMID: 35766979 PMCID: PMC9247717 DOI: 10.1084/jem.20211637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 01/17/2022] [Accepted: 03/28/2022] [Indexed: 02/03/2023] Open
Abstract
Rap1 GTPase drives assembly of the Mig-10/RIAM/Lamellipodin (MRL protein)-integrin-talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag-based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (Ptsn), a regulatory subunit of protein phosphatase 1, is a component of the complex. Ptsn mediates dephosphorylation of Rap1, thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes Ptsn, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18-/- mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable, in part, to defective activation of integrins αLβ2 and α4β7. Ppp1r18-/- T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, Ptsn enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of Ptsn ameliorates T cell-mediated colitis.
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Affiliation(s)
- Ho-Sup Lee
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Hao Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Frédéric Lagarrigue
- Department of Medicine, University of California, San Diego, La Jolla, CA
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
| | - Sarah Hyun Ji Kim
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Jay W. Fox
- School of Medicine, University of Virginia, Charlottesville, VA
| | | | | | - Mark H. Ginsberg
- Department of Medicine, University of California, San Diego, La Jolla, CA
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13
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Intestinal homeostasis in autoimmune liver diseases. Chin Med J (Engl) 2022; 135:1642-1652. [PMID: 36193976 PMCID: PMC9509077 DOI: 10.1097/cm9.0000000000002291] [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] [Indexed: 02/04/2023] Open
Abstract
ABSTRACT Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.
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14
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Liu N, Sadlon T, Wong YY, Pederson S, Breen J, Barry SC. 3DFAACTS-SNP: using regulatory T cell-specific epigenomics data to uncover candidate mechanisms of type 1 diabetes (T1D) risk. Epigenetics Chromatin 2022; 15:24. [PMID: 35773720 PMCID: PMC9244893 DOI: 10.1186/s13072-022-00456-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 06/06/2022] [Indexed: 11/26/2022] Open
Abstract
Background Genome-wide association studies (GWAS) have enabled the discovery of single nucleotide polymorphisms (SNPs) that are significantly associated with many autoimmune diseases including type 1 diabetes (T1D). However, many of the identified variants lie in non-coding regions, limiting the identification of mechanisms that contribute to autoimmune disease progression. To address this problem, we developed a variant filtering workflow called 3DFAACTS-SNP to link genetic variants to target genes in a cell-specific manner. Here, we use 3DFAACTS-SNP to identify candidate SNPs and target genes associated with the loss of immune tolerance in regulatory T cells (Treg) in T1D. Results Using 3DFAACTS-SNP, we identified from a list of 1228 previously fine-mapped variants, 36 SNPs with plausible Treg-specific mechanisms of action. The integration of cell type-specific chromosome conformation capture data in 3DFAACTS-SNP identified 266 regulatory regions and 47 candidate target genes that interact with these variant-containing regions in Treg cells. We further demonstrated the utility of the workflow by applying it to three other SNP autoimmune datasets, identifying 16 Treg-centric candidate variants and 60 interacting genes. Finally, we demonstrate the broad utility of 3DFAACTS-SNP for functional annotation of all known common (> 10% allele frequency) variants from the Genome Aggregation Database (gnomAD). We identified 9376 candidate variants and 4968 candidate target genes, generating a list of potential sites for future T1D or other autoimmune disease research. Conclusions We demonstrate that it is possible to further prioritise variants that contribute to T1D based on regulatory function, and illustrate the power of using cell type-specific multi-omics datasets to determine disease mechanisms. Our workflow can be customised to any cell type for which the individual datasets for functional annotation have been generated, giving broad applicability and utility. Supplementary Information The online version contains supplementary material available at 10.1186/s13072-022-00456-5.
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Affiliation(s)
- Ning Liu
- South Australian Health and Medical Research Institute, Adelaide, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, Australia.,Bioinformatics Hub, School of Biological Sciences, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Timothy Sadlon
- Robinson Research Institute, University of Adelaide, Adelaide, Australia.,Women's and Children's Health Network, Women's and Children's Hospital, Adelaide, Australia
| | - Ying Y Wong
- Robinson Research Institute, University of Adelaide, Adelaide, Australia.,Women's and Children's Health Network, Women's and Children's Hospital, Adelaide, Australia
| | - Stephen Pederson
- Bioinformatics Hub, School of Biological Sciences, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - James Breen
- South Australian Health and Medical Research Institute, Adelaide, Australia. .,Robinson Research Institute, University of Adelaide, Adelaide, Australia. .,Bioinformatics Hub, School of Biological Sciences, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia. .,Black Ochre Data Labs, Indigenous Genomics, Telethon Kids Institute, Adelaide, Australia. .,John Curtin School of Medical Research, Australian National University, Canberra, Australia.
| | - Simon C Barry
- Robinson Research Institute, University of Adelaide, Adelaide, Australia.,Women's and Children's Health Network, Women's and Children's Hospital, Adelaide, Australia
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15
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Integrin Regulators in Neutrophils. Cells 2022; 11:cells11132025. [PMID: 35805108 PMCID: PMC9266208 DOI: 10.3390/cells11132025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 02/01/2023] Open
Abstract
Neutrophils are the most abundant leukocytes in humans and are critical for innate immunity and inflammation. Integrins are critical for neutrophil functions, especially for their recruitment to sites of inflammation or infections. Integrin conformational changes during activation have been heavily investigated but are still not fully understood. Many regulators, such as talin, Rap1-interacting adaptor molecule (RIAM), Rap1, and kindlin, are critical for integrin activation and might be potential targets for integrin-regulating drugs in treating inflammatory diseases. In this review, we outline integrin activation regulators in neutrophils with a focus on the above critical regulators, as well as newly discovered modulators that are involved in integrin activation.
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16
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Wen L, Moser M, Ley K. Molecular mechanisms of leukocyte β2 integrin activation. Blood 2022; 139:3480-3492. [PMID: 35167661 PMCID: PMC10082358 DOI: 10.1182/blood.2021013500] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/06/2022] [Indexed: 11/20/2022] Open
Abstract
Integrins are transmembrane receptors that mediate cell-cell and cell-extracellular matrix adhesion. Although all integrins can undergo activation (affinity change for ligands), the degree of activation is most spectacular for integrins on blood cells. The β2 integrins are exclusively expressed on the surface of all leukocytes including neutrophils, lymphocytes, and monocytes. They are essential for many leukocyte functions and are strictly required for neutrophil arrest from rolling. The inside-out integrin activation process receives input from chemokine receptors and adhesion molecules. The integrin activation pathway involves many cytoplasmic signaling molecules such as spleen tyrosine kinase, other kinases like Bruton's tyrosine kinase, phosphoinositide 3-kinases, phospholipases, Rap1 GTPases, and the Rap1-GTP-interacting adapter molecule. These signaling events ultimately converge on talin-1 and kindlin-3, which bind to the integrin β cytoplasmic domain and induce integrin conformational changes: extension and high affinity for ligand. Here, we review recent structural and functional insights into how talin-1 and kindlin-3 enable integrin activation, with a focus on the distal signaling components that trigger β2 integrin conformational changes and leukocyte adhesion under flow.
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Affiliation(s)
- Lai Wen
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
| | - Markus Moser
- Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Klaus Ley
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA
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17
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Sun H, Lagarrigue F, Ginsberg MH. The Connection Between Rap1 and Talin1 in the Activation of Integrins in Blood Cells. Front Cell Dev Biol 2022; 10:908622. [PMID: 35721481 PMCID: PMC9198492 DOI: 10.3389/fcell.2022.908622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 01/13/2023] Open
Abstract
Integrins regulate the adhesion and migration of blood cells to ensure the proper positioning of these cells in the environment. Integrins detect physical and chemical stimuli in the extracellular matrix and regulate signaling pathways in blood cells that mediate their functions. Integrins are usually in a resting state in blood cells until agonist stimulation results in a high-affinity conformation ("integrin activation"), which is central to integrins' contribution to blood cells' trafficking and functions. In this review, we summarize the mechanisms of integrin activation in blood cells with a focus on recent advances understanding of mechanisms whereby Rap1 regulates talin1-integrin interaction to trigger integrin activation in lymphocytes, platelets, and neutrophils.
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Affiliation(s)
- Hao Sun
- Department of Medicine, University of California San Diego, San Diego, CA, United States
| | - Frederic Lagarrigue
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, Toulouse, France
| | - Mark H. Ginsberg
- Department of Medicine, University of California San Diego, San Diego, CA, United States
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18
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LFA1 Activation: Insights from a Single-Molecule Approach. Cells 2022; 11:cells11111751. [PMID: 35681446 PMCID: PMC9179313 DOI: 10.3390/cells11111751] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Integrin LFA1 is a cell adhesion receptor expressed exclusively in leukocytes, and plays crucial roles in lymphocyte trafficking, antigen recognition, and effector functions. Since the discovery that the adhesiveness of LFA1 can be dynamically changed upon stimulation, one challenge has been understanding how integrins are regulated by inside-out signaling coupled with macromolecular conformational changes, as well as ligand bindings that transduce signals from the extracellular domain to the cytoplasm in outside-in signaling. The small GTPase Rap1 and integrin adaptor proteins talin1 and kindlin-3 have been recognized as critical molecules for integrin activation. However, their cooperative regulation of integrin adhesiveness in lymphocytes requires further research. Recent advances in single-molecule imaging techniques have revealed dynamic molecular processes in real-time and provided insight into integrin activation in cellular environments. This review summarizes integrin regulation and discusses new findings regarding the bidirectionality of LFA1 activation and signaling processes in lymphocytes.
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19
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Zheng H, Chen Y, Li J, Li H, Zhao X, Li J, Yang F, Li Y, Liu C, Qin L, Zuo Y, Zhang Q, He Z, Shi H, Li Q, Liu L. Longitudinal analyses reveal distinct immune response landscapes in lung and intestinal tissues from SARS-CoV-2-infected rhesus macaques. Cell Rep 2022; 39:110864. [PMID: 35594870 PMCID: PMC9080054 DOI: 10.1016/j.celrep.2022.110864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/04/2022] [Accepted: 05/02/2022] [Indexed: 11/24/2022] Open
Abstract
The pathological and immune response of individuals with COVID-19 display different dynamics in lung and intestine. Here, we depict the single-cell transcriptional atlas of longitudinally collected lung and intestinal tissue samples from SARS-CoV-2-infected monkeys at 3 to 10 dpi. We find that intestinal enterocytes are degraded at 3 days post-infection but recovered rapidly, revealing that infection has mild effects on the intestine. Crucially, we observe suppression of the inflammatory response and tissue damage related to B-cell and Paneth cell accumulation in the intestines, although T cells are activated in the SARS-CoV-2 infection. Compared with that in the lung, the expression of interferon response-related genes is inhibited, and inflammatory factor secretion is reduced in the intestines. Our findings indicate an imbalance of immune dynamic in intestinal mucosa during SARS-CoV-2 infection, which may underlie ongoing rectal viral shedding and mild tissue damage.
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20
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Lagarrigue F, Tan B, Du Q, Fan Z, Lopez-Ramirez MA, Gingras AR, Wang H, Qi W, Sun H. Direct Binding of Rap1 to Talin1 and to MRL Proteins Promotes Integrin Activation in CD4 + T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1378-1388. [PMID: 35197328 PMCID: PMC9644409 DOI: 10.4049/jimmunol.2100843] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/27/2021] [Indexed: 12/26/2022]
Abstract
Agonist-induced Rap1 GTP loading results in integrin activation involved in T cell trafficking and functions. MRL proteins Rap1-interacting adapter molecule (RIAM) and lamellipodin (LPD) are Rap1 effectors that can recruit talin1 to integrins, resulting in integrin activation. Recent work also implicates direct Rap1-talin1 interaction in integrin activation. Here, we analyze in mice the connections between Rap1 and talin1 that support integrin activation in conventional CD4+ T (Tconv) and CD25HiFoxp3+CD4+ regulatory T (Treg) cells. Talin1(R35E, R118E) mutation that disrupts both Rap1 binding sites results in a partial defect in αLβ2, α4β1, and α4β7 integrin activation in both Tconv and Treg cells with resulting defects in T cell homing. Talin1(R35E,R118E) Tconv manifested reduced capacity to induce colitis in an adoptive transfer mouse model. Loss of RIAM exacerbates the defects in Treg cell function caused by the talin1(R35E,R118E) mutation, and deleting both MRL proteins in combination with talin1(R35E,R118E) phenocopy the complete lack of integrin activation observed in Rap1a/b-null Treg cells. In sum, these data reveal the functionally significant connections between Rap1 and talin1 that enable αLβ2, α4β1, and α4β7 integrin activation in CD4+ T cells.
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Affiliation(s)
- Frederic Lagarrigue
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, Toulouse, France
| | - Boyang Tan
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Qinyi Du
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Zhichao Fan
- Department of Immunology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT
| | | | - Alexandre R Gingras
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Hsin Wang
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Weiwei Qi
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Hao Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
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21
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Zhang JJ, Wang JQ, Xu X, Zhang LD, Zhang CP, Lu WL, Gu WQ, Dong ZY, Xiao Y, Xia ZW. Circulating circular RNA profiles associated with celiac disease seropositivity in children with type 1 diabetes. Front Pediatr 2022; 10:960825. [PMID: 36210930 PMCID: PMC9537605 DOI: 10.3389/fped.2022.960825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION The frequency of celiac disease autoantibody (CDAb) positivity in type 1 diabetes (T1D) has increased due to unclear mechanisms, including autoimmune injury. Circular ribonucleic acids (circRNAs) participate in autoimmune diseases, but the roles of circRNAs in T1D with CDAbs are currently unknown. This study aimed to determine the frequency of CDAbs in Chinese children with T1D and describe the relationship between CDAbs and circRNAs. MATERIALS AND METHODS Eighty patients diagnosed with T1D were screened for CDAbs and CD-predisposing genes, and circRNAs in peripheral blood mononuclear cells (PBMCs) were collected from 47 patients. The Gene Expression Omnibus (GEO) database was searched for candidate circRNAs in related studies on T1D PBMCs. Data on clinical characteristics (i.e., blood glucose control, residual islet function, and daily insulin dosage) and immunophenotypes (i.e., islet autoantibodies and immune cell subsets) were collected. RESULTS In total, 35.0% of patients were positive for CDAbs. CD-predisposing genes accounted for 52.5% of the genes, and no significant difference in frequency was found between the CDAb-positive (CDAb+) and CDAb-negative (CDAb-) groups. In addition, among the differentially expressed circRNAs from the GEO database, five highly conserved circRNAs homologous to humans and mice were screened, and only the expression of hsa_circ_0004564 in the CDAb+ group significantly decreased (CDAb+ vs. CDAb-:1.72 ± 1.92 vs. 11.12 ± 8.59, p = 6.0 × 10-6), while the expression of hsa_circ_0004564 was upregulated in the general T1D population. Moreover, its parental gene RAPH1 was significantly upregulated (CDAb+ vs. CDAb-:1.26 ± 0.99 vs. 0.61 ± 0.46, p = 0.011). Importantly, the positive correlation between hsa_circ_0004564 and CD3+ cells was validated in children with T1D after adjustments for CDAbs (p = 0.029), while there were no correlations between hsa_circ_0004564 and clinical characteristics or other immune cell subsets (i.e., CD4+ T cells, CD8+ T cells, and natural killer cells). CONCLUSION This study highlights the importance of screening for CD in Chinese children with T1D, considering the high prevalence of CDAb positivity and CD-predisposing genes. The profile of candidate circRNAs in children with T1D with CDAbs was different from that in previous reports on general T1D patients from the GEO database. Moreover, hsa_circ_0004564 and its parental gene RAPH1 may be new targets for studying immune mechanisms in children with T1D and CD.
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Affiliation(s)
- Juan-Juan Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jun-Qi Wang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xu Xu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Li-Dan Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Cai-Ping Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wen-Li Lu
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Wei-Qiong Gu
- Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhi-Ya Dong
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yuan Xiao
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhen-Wei Xia
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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22
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Sari-Ak D, Torres-Gomez A, Yazicioglu YF, Christofides A, Patsoukis N, Lafuente EM, Boussiotis VA. Structural, biochemical, and functional properties of the Rap1-Interacting Adaptor Molecule (RIAM). Biomed J 2021; 45:289-298. [PMID: 34601137 PMCID: PMC9250098 DOI: 10.1016/j.bj.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/16/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Leukocytes, the leading players of immune system, are involved in innate and adaptive immune responses. Leukocyte adhesion to endothelial cells during transmigration or to antigen presenting cells during T cell activation, requires integrin activation through a process termed inside-out integrin signaling. In hematopoietic cells, Rap1 and its downstream effector RIAM (Rap1-interacting adaptor molecule) form a cornerstone for inside-out integrin activation. The Rap1/RIAM pathway is involved in signal integration for activation, actin remodeling and cytoskeletal reorganization in T cells, as well as in myeloid cell differentiation and function. RIAM is instrumental for phagocytosis, a process requiring particle recognition, cytoskeletal remodeling and membrane protrusion for engulfment and digestion. In the present review, we discuss the structural and molecular properties of RIAM and the recent discoveries regarding the functional role of the Rap1/RIAM module in hematopoietic cells.
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Affiliation(s)
- Duygu Sari-Ak
- Department of Medical Biology, School of Medicine, University of Health Sciences, Istanbul, Turkey, 34668
| | - Alvaro Torres-Gomez
- School of Medicine, Unit of Immunology, Complutense University of Madrid, 28040, Madrid, Spain
| | - Yavuz-Furkan Yazicioglu
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK
| | - Anthos Christofides
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, 02215; Department of Medicine, Harvard Medical School, Boston, MA, 02215; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215
| | - Nikolaos Patsoukis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, 02215; Department of Medicine, Harvard Medical School, Boston, MA, 02215; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215
| | - Esther M Lafuente
- School of Medicine, Unit of Immunology, Complutense University of Madrid, 28040, Madrid, Spain
| | - Vassiliki A Boussiotis
- Division of Hematology-Oncology, Harvard Medical School, Boston, MA, 02215; Department of Medicine, Harvard Medical School, Boston, MA, 02215; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215.
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23
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Bromberger T, Klapproth S, Rohwedder I, Weber J, Pick R, Mittmann L, Min-Weißenhorn SJ, Reichel CA, Scheiermann C, Sperandio M, Moser M. Binding of Rap1 and Riam to Talin1 Fine-Tune β2 Integrin Activity During Leukocyte Trafficking. Front Immunol 2021; 12:702345. [PMID: 34489950 PMCID: PMC8417109 DOI: 10.3389/fimmu.2021.702345] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/04/2021] [Indexed: 01/13/2023] Open
Abstract
β2 integrins mediate key processes during leukocyte trafficking. Upon leukocyte activation, the structurally bent β2 integrins change their conformation towards an extended, intermediate and eventually high affinity conformation, which mediate slow leukocyte rolling and firm arrest, respectively. Translocation of talin1 to integrin adhesion sites by interactions with the small GTPase Rap1 and the Rap1 effector Riam precede these processes. Using Rap1 binding mutant talin1 and Riam deficient mice we show a strong Riam-dependent T cell homing process to lymph nodes in adoptive transfer experiments and by intravital microscopy. Moreover, neutrophils from compound mutant mice exhibit strongly increased rolling velocities to inflamed cremaster muscle venules compared to single mutants. Using Hoxb8 cell derived neutrophils generated from the mutant mouse strains, we show that both pathways regulate leukocyte rolling and adhesion synergistically by inducing conformational changes of the β2 integrin ectodomain. Importantly, a simultaneous loss of both pathways results in a rolling phenotype similar to talin1 deficient neutrophils suggesting that β2 integrin regulation primarily occurs via these two pathways.
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Affiliation(s)
- Thomas Bromberger
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
| | - Sarah Klapproth
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany
| | - Ina Rohwedder
- Walter Brendel Center of Experimental Medicine (WBex), Biomedical Center (BMC), Ludwig-Maximilians-Universität München, Martinsried, Germany
| | - Jasmin Weber
- Walter Brendel Center of Experimental Medicine (WBex), Biomedical Center (BMC), Ludwig-Maximilians-Universität München, Martinsried, Germany
| | - Robert Pick
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Laura Mittmann
- Walter Brendel Centre of Experimental Medicine (WBex), Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
- Department of Otorhinolaryngology, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Christoph A. Reichel
- Walter Brendel Centre of Experimental Medicine (WBex), Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
- Department of Otorhinolaryngology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Christoph Scheiermann
- Walter Brendel Center of Experimental Medicine (WBex), Biomedical Center (BMC), Ludwig-Maximilians-Universität München, Martinsried, Germany
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Markus Sperandio
- Walter Brendel Center of Experimental Medicine (WBex), Biomedical Center (BMC), Ludwig-Maximilians-Universität München, Martinsried, Germany
| | - Markus Moser
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
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24
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Sun H, Hu L, Fan Z. β2 integrin activation and signal transduction in leukocyte recruitment. Am J Physiol Cell Physiol 2021; 321:C308-C316. [PMID: 34133240 DOI: 10.1152/ajpcell.00560.2020] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Leukocyte recruitment is a critical step in the pathogenesis of inflammatory and immunological responses. Cell adhesion molecules (CAMs) are involved in controlling cell movements and the recruitment process, and the integrin family of CAMs plays a key role. During cell movement, integrin function is dynamically and precisely regulated. However, this balance might be broken under pathological conditions. Thus, the functional regulation and molecular mechanisms of integrins related to diseases are often a focus of research. Integrin β2 is one of the most commonly expressed integrins in leukocytes that mediate leukocyte adhesion and migration, and it plays an important role in immune responses and inflammation. In this review, we focus on specific functions of integrin β2 in leukocyte recruitment, the conformational changes and signal transduction of integrin β2 activation, the similarities between murine and human factors, and how new insights into these processes can inform future therapies for inflammation and immune diseases.
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Affiliation(s)
- Hao Sun
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Liang Hu
- Cardiovascular Institute of Zhengzhou University, Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhichao Fan
- Department of Immunology, School of Medicine, UConn Health, Farmington, Connecticut
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25
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Moreau JM, Gouirand V, Rosenblum MD. T-Cell Adhesion in Healthy and Inflamed Skin. JID INNOVATIONS 2021; 1:100014. [PMID: 35024681 PMCID: PMC8669513 DOI: 10.1016/j.xjidi.2021.100014] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 04/06/2021] [Indexed: 12/24/2022] Open
Abstract
The diverse populations of tissue-resident and transitory T cells present in the skin share a common functional need to enter, traverse, and interact with their environment. These processes are largely dependent on the regulated expression of adhesion molecules, such as selectins and integrins, which mediate bidirectional interactions between immune cells and skin stroma. Dysregulation and engagement of adhesion pathways contribute to ectopic T-cell activity in tissues, leading to the initiation and/or exacerbation of chronic inflammation. In this paper, we review how the molecular interactions supported by adhesion pathways contribute to T-cell dynamics and function in the skin. A comprehensive understanding of the molecular mechanisms underpinning T-cell adhesion in inflammatory skin disorders will facilitate the development of novel tissue-specific therapeutic strategies.
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Key Words
- AD, atopic dermatitis
- BM, basement membrane
- DC, dendritic cell
- DETC, dendritic epidermal γδ T cell
- ECM, extracellular matrix
- HF, hair follicle
- JC, John Cunningham
- LAD, leukocyte adhesion deficiency
- PML, progressive multifocal leukoencephalopathy
- Th, T helper
- Treg, regulatory T cell
- Trm, tissue-resident memory
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Affiliation(s)
- Joshua M. Moreau
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Victoire Gouirand
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Michael D. Rosenblum
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
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26
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Lagarrigue F, Gingras AR. Src-mediated phosphorylation of RIAM promotes integrin activation. Structure 2021; 29:305-307. [PMID: 33798425 DOI: 10.1016/j.str.2021.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
In this issue of Structure, Cho et al. (2020) identified an intermolecular interaction between two RIAM pleckstrin homology (PH) domains that masks the phosphoinositide-binding site, and that phosphorylation by Src unmasks the PH domain. This provides an explanation of how RIAM plasma membrane translocation is regulated to promote integrin activation.
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Affiliation(s)
- Frédéric Lagarrigue
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Alexandre R Gingras
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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27
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Sun H, Zhi K, Hu L, Fan Z. The Activation and Regulation of β2 Integrins in Phagocytes and Phagocytosis. Front Immunol 2021; 12:633639. [PMID: 33868253 PMCID: PMC8044391 DOI: 10.3389/fimmu.2021.633639] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
Phagocytes, which include neutrophils, monocytes, macrophages, and dendritic cells, protect the body by removing foreign particles, bacteria, and dead or dying cells. Phagocytic integrins are greatly involved in the recognition of and adhesion to specific antigens on cells and pathogens during phagocytosis as well as the recruitment of immune cells. β2 integrins, including αLβ2, αMβ2, αXβ2, and αDβ2, are the major integrins presented on the phagocyte surface. The activation of β2 integrins is essential to the recruitment and phagocytic function of these phagocytes and is critical for the regulation of inflammation and immune defense. However, aberrant activation of β2 integrins aggravates auto-immune diseases, such as psoriasis, arthritis, and multiple sclerosis, and facilitates tumor metastasis, making them double-edged swords as candidates for therapeutic intervention. Therefore, precise regulation of phagocyte activities by targeting β2 integrins should promote their host defense functions with minimal side effects on other cells. Here, we reviewed advances in the regulatory mechanisms underlying β2 integrin inside-out signaling, as well as the roles of β2 integrin activation in phagocyte functions.
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Affiliation(s)
- Hao Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Kangkang Zhi
- Department of Vascular Surgery, Changzheng Hospital, Shanghai, China
| | - Liang Hu
- Department of Cardiology, Cardiovascular Institute of Zhengzhou University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhichao Fan
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT, United States
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28
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Su B, Wu J. Phosphorylation of RIAM Activates Its Adaptor Function in Mediating Integrin Signaling. JOURNAL OF CELLULAR SIGNALING 2021; 2:103-110. [PMID: 35128538 PMCID: PMC8813058 DOI: 10.33696/signaling.2.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Integrins are cellular receptors that regulate cell adhesion and many other cellular functions. Integrins can be activated via an "inside-out pathway" that is promoted by RAP1 GTPase. RAP1-GTP-Interacting Adaptor Molecular (RIAM) mediates integrin activation by linking RAP1 GTPase to talin, an integrin activator. RIAM's function in integrin signaling is tightly regulated. In this commentary, we review recent studies of the molecular mechanisms underlying RIAM autoinhibition via both intramolecular interaction and oligomer assembly, and the phosphorylation-dependent activation of RIAM.
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Affiliation(s)
| | - Jinhua Wu
- Correspondence should be addressed to Jinhua Wu;
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