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The Activation and Regulation of Β2 Integrins in Phagocytes And

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The Activation and Regulation of Β2 Integrins in Phagocytes And MINI REVIEW published: 31 March 2021 doi: 10.3389/fimmu.2021.633639 The Activation and Regulation of b2 Integrins in Phagocytes and Phagocytosis † † Hao Sun 1 , Kangkang Zhi 2 , Liang Hu 3 and Zhichao Fan 4* 1 Department of Medicine, University of California, San Diego, La Jolla, CA, United States, 2 Department of Vascular Surgery, Changzheng Hospital, Shanghai, China, 3 Department of Cardiology, Cardiovascular Institute of Zhengzhou University, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, 4 Department of Immunology, School of Medicine, UConn Health, Farmington, CT, United States 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 Edited by: immune cells. b2 integrins, including aLb2, aMb2, aXb2, and aDb2, are the major Valentin Jaumouille´ , integrins presented on the phagocyte surface. The activation of b2 integrins is essential to Simon Fraser University, Canada the recruitment and phagocytic function of these phagocytes and is critical for the Reviewed by: fl Esther M. Lafuente, regulation of in ammation and immune defense. However, aberrant activation of b2 Complutense University of Madrid, integrins aggravates auto-immune diseases, such as psoriasis, arthritis, and multiple Spain sclerosis, and facilitates tumor metastasis, making them double-edged swords as Pontus Nordenfelt, Lund University, Sweden candidates for therapeutic intervention. Therefore, precise regulation of phagocyte Mehmet Sen, activities by targeting b2 integrins should promote their host defense functions with University of Houston, United States minimal side effects on other cells. Here, we reviewed advances in the regulatory *Correspondence: Zhichao Fan mechanisms underlying b2 integrin inside-out signaling, as well as the roles of b2 [email protected] integrin activation in phagocyte functions. †These authors have contributed Keywords: b2 integrins, integrin activation, integrin adaptors, phagocytes, phagocytosis equally to this work Specialty section: This article was submitted to INTRODUCTION Molecular Innate Immunity, a section of the journal Phagocytosis is the mechanism by which microorganisms are engulfed and killed, and it is the main Frontiers in Immunology process by which immune cells disassemble pathogens to present antigens. This is important for the Received: 25 November 2020 innate immune response and initiating adaptive immune responses. Phagocytosis is a special form Accepted: 11 March 2021 of cell endocytosis, whereby cells ingest solid particles through vesicles, including microbial Published: 31 March 2021 pathogens (1–3). While most cells are capable of phagocytosis, the professional phagocytes of the Citation: immune system, such as macrophages, monocytes, neutrophils, and dendritic cells, excel in this Sun H, Zhi K, Hu L and Fan Z (2021) process (4). During phagocytic uptake, phagocytes use receptors to interact with particles and The Activation and Regulation mediate signals that encapsulate the particle within the membrane, leading to complete engulfment of b2 Integrins in Phagocytes and Phagocytosis. (5, 6). Particle recognition and uptake are conducted by a receptor ligation zipper-like process that Front. Immunol. 12:633639. involves several types of receptors, such as integrins, Fcg receptors (FcgRs), and scavenger receptors doi: 10.3389/fimmu.2021.633639 (1, 7). Frontiers in Immunology | www.frontiersin.org 1 March 2021 | Volume 12 | Article 633639 Sun et al. Phagocyte b2 Integrins Integrins are essential cell-surface adhesion molecules that are similar to LAD-I (28). These patients end up suffering from widely expressed on cell membranes. As cell adhesion receptors, recurrent life-threatening infections (29). Overaggressive b2 integrins transduce intracellular and bidirectional intercellular integrin activation leads to excessive inflammation and associated signals (8, 9), and are crucial for immune system functions (10, tissue damage (30). 11). In recent years, great progress has been made in elucidating Integrin aLb2 is critical for the adhesion of blood phagocytes integrin signal transduction mechanisms in phagocytes. b2 (such as neutrophils and monocytes) to the vascular endothelium integrins, such as complement receptor 3 (CR3, also known as (31–35), as well as intravascular patrolling of monocytes (36, 37) integrin aMb2, CD11b/CD18, macrophage-1 antigen, or Mac-1) and transendothelial migration of neutrophils (38, 39). Integrin and complement receptor 4 (CR4, also known as integrin aXb2, aMb2 is involved in cell adhesion, cell migration, phagocytosis, and CD11c/CD18, or p150/95), are highly expressed in phagocytes degranulation of phagocytes (14, 24–26, 37, 40). Integrin aMb2 and are important for phagocytosis. This review focuses on the recognizes various structurally and functionally different ligands, role of b2 integrin activation and signaling during both adhesion including extracellular matrix (ECM)-associated ligands that are and phagocytosis. We highlight the inside-out signaling basis of released from damaged cells during inflammatory responses, such b2 integrin function during adhesion and phagocytosis and as intercellular adhesion molecule 1 (ICAM-1), glycoprotein Ib-IX, propose that b2 integrin-mediated phagocytosis is a great and junctional adhesion molecule 3 (JAM-3) (41–45). Both aMb2 model to understand functional regulation of integrins. and aXb2 can bind to complement component iC3b and are crucial for RhoA-dependent phagocytosis in phagocytes (46–48). The differences between these two integrins have been studied in b2 INTEGRINS EXPRESSED aMandaXknockoutmice(Table 1). aMb2 plays a major role in BY PHAGOCYTES recruitment of polymorphonuclear neutrophil (PMN) to bacterial and fungal pathogens. aXb2 plays a central role in monocyte- and b2 integrins play a major role in regulating phagocyte adhesion and macrophage-mediated inflammatory functions, as shown by aXb2 migration to inflamed organs and other immunological processes, deficiency that abrogated the recruitment of monocytes and such as phagocytosis (12, 13)(Table 1). In mammals, professional macrophages to sites of inflammation or infection and reduced phagocytes express complement receptors, some of which are b2 the ability of these cells to kill/phagocytose pathogens (17). Integrin integrins, such as CR3 and CR4, which are critical for anti-pathogen aDb2 is rarely expressed on peripheral blood phagocytes but is defense and inflammation regulation. Phagocytes like monocytes significantly up-regulated on macrophages during inflammation and macrophages express all four b2 integrin family members: CR3, (e.g., atherosclerosis) (19). Integrin aDb2andaMb2showsome CR4, aLb2 (also known as CD11a/CD18, lymphocyte function- similarities in many functions and share some ligands, such as associated antigen 1, or LFA-1), and aDb2 (CD11d/CD18) (23). ICAM-1, ICAM-2, ICAM-4, fibrinogen, collagen, iC3b, heparin, The activation of b2 integrins is involved in multiple functions of GPIba,Thy-1,andplasminogen(49, 50). Recently, it was shown phagocytes, such as cell adhesion, locomotion, exocytosis, and that b2 integrins are required for both monocyte and phagocytosis (14, 24–26). The central role of b2 integrins in hematopoietic functions, and lower b2 integrin expression is immunity is highlighted by the fact that patients with leukocyte associated with more severe schistosomiasis in mice (51). adhesion deficiency type I (LAD-I) syndrome, who lack b2integrin b2 integrins are important for the fusion of human (52) but expression, are particularly prone to bacterial infections (27). LAD- not mouse (53) macrophages; Macrophage fusion happens III (leukocyte adhesion deficiency type III) patients have mutations during chronic infection of persistent pathogens or encounters in kindlin-3 (an integrin binding protein) and show a deficiency in with nondegradable foreign objects, and results in the formation integrin b2 activation, leading to an adhesion defect of phagocytes of multinucleated giant cells. Human monocyte-derived TABLE 1 | Distribution of b2 integrins and phenotypes of engineered gene knockout mice. Distribution Phenotypes of knockout mice aLb2 All leukocytes but predominates on Defective adhesion and migration of neutrophils, monocytes, and macrophages; impaired neutrophil (14–16) lymphocytes chemotaxis; a defect in TNF-a-induced neutrophil and monocyte extravasation from blood vessels; a defect in the induction of peripheral immune responses; reduced NK cytotoxicity. aMb2 Abundant on myeloid cells, monocytes/ Defective recruitment of neutrophils and mast cells to bacterial and fungal pathogens; a defect in (14, 15) macrophages, neutrophils, NK cells, neutrophil binding to fibrinogen and degranulation; impaired mast cell development and innate immunity; fibrocytes, mast cells, B cells, CD8+ T a defect in macrophage egression from the peritoneal cavity. cells, and CD4+ gd T cells aXb2 Abundant on myeloid dendritic cells, Defect in intraperitoneal recruitment and adhesive functions of monocytes and macrophages and their (17, 18) monocytes/macrophages; expressed on ability to kill/phagocytose pathogens. human NK cells and lymphocyte subpopulations aDb2 Abundant on myeloid cells, Defective macrophage retention and reduced neutrophil accumulation in the atherosclerotic
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