Trends in Immunology
Neutrophil β2 integrins: moderators of life or death decisions
Introduction
Neutrophils are essential for host defense, in which they are responsible for eliminating invading pathogens through a process requiring neutrophil recruitment, chemotaxis and the engulfment and destruction of the offending microbe. However, neutrophil-derived proteinases and reactive oxygen species (ROS), which are required for the elimination of microbes, are also capable of inflicting damage to surrounding tissue. In some cases, these harmful consequences become dominant, such as in bacterial meningitis, acute glomerulonephritis, ischemia–reperfusion injury, adult respiratory distress syndrome and hypersensitivity reactions 1, 2. Neutrophil accumulation in inflamed tissues is the balance of the rate of their recruitment and removal. These two processes need to be regulated exquisitely to both maximize host defense and limit the potentially destructive effects of neutrophil cytotoxicity. Neutrophil recruitment is supported by leukocyte adhesion molecules and chemokines and cytokines expressed in and around blood vessels at the sites of inflammation [3]. Neutrophils are cleared from tissues by apoptosis and subsequent phagocytosis by resident macrophages, a process that promotes the resolution of the inflammatory response 4, 5, 6.
β2 integrins are leukocyte-specific integrins that are required for neutrophil adhesion and transmigration across the activated endothelium, as well as for other adhesion-dependent neutrophil functions, such as the phagocytic clearance of pathogens [7]. Moreover, β2 integrins have been implicated recently in the regulation of neutrophil apoptosis. Published data suggest a model wherein β2 integrin engagement during neutrophil transmigration extends the survival and thus the pool of functional neutrophils in tissues, whereas β2 integrin-dependent phagocytosis of microbes accelerates apoptosis and might be a potent mechanism to eliminate neutrophils that have reached the end of their useful life span (Figure 1). Following β2 integrin engagement, the fate of the neutrophil is also influenced by the inflammatory mediators generated during the inflammatory response (Figure 2). This review will discuss data in support of these models. In addition, in vivo evidence for a possible role for neutrophil apoptosis and clearance in inflammation is discussed.
Section snippets
Constitutive neutrophil apoptosis
Apoptosis is a genetically regulated form of cell death, which is important for normal embryonic development and cell turnover in adult organisms. Apoptosis has significant roles in the control of the immune response, and its dysregulation, which is most described in T cells, might lead to several human diseases, including autoimmune diseases and immunodeficiencies. Neutrophil apoptosis is crucial for the successful resolution of inflammation. Unlike T cells, which have an estimated life span
β2 (CD18) integrins in inflammation
The β2 integrin family is composed of four integrin family members, CD11a/CD18 [lymphocyte function-associated antigen-1 (LFA-1)], CD11b/CD18 (Mac-1), CD11c/CD18 and CD11d/CD18, which are heterodimers composed of a unique α (CD11) subunit complexed to a common β2 (CD18) subunit. These integrins have crucial roles in various neutrophil functions that are required for the containment and elimination of infection. They are present in an inactive state on circulating leukocytes, however, on
Engagement of Mac-1 promotes cell survival: death-inducing agonists shift the balance towards cell death
Neutrophil adhesion to Mac-1 ligands, fibrinogen and ICAM-1, extends the life span of neutrophils [28]. The delay in apoptosis in response to ICAM-1 adhesion is attributed to the Ser–Thr kinase Akt. Akt is activated through phosphatidylinositide 3-kinase (PI-3K)-generated lipid products and inhibits mitochondrial pathways of apoptosis in several cell types [29]. Fibrinogen-mediated delay in neutrophil apoptosis is also reported to be dependent on Akt, and in addition, is reliant on MAPK–ERK
Mac-1 promotes apoptosis following neutrophil phagocytosis
CD11b/CD18-deficiency in mice result in increased accumulation of neutrophils in response to chemical-induced peritonitis that is associated with a reduction in neutrophil apoptosis. By contrast, the number of circulating neutrophils and apoptotic cell death in this population are unaffected by Mac-1 deficiency, suggesting that Mac-1 specifically modulates apoptosis of neutrophils accumulated in inflamed tissues [41]. A possible mechanism for this Mac-1-dependent apoptosis was revealed by in
Transcriptional regulation of PICD
Cell death following phagocytosis of complement C3bi-opsonized targets is regulated at the transcriptional level. Neutrophil phagocytosis of C3bi-coated beads rapidly induced changes in the mRNA levels of several apoptosis-related proteins [58]. This is consistent with earlier reports of rapid changes in the expression patterns of apoptosis-regulating proteins following exposure of neutrophils to complement-opsonized bacteria [59]. Although the role of Mac-1 was not explicitly analyzed in both
Concluding remarks and perspectives
In summary, Mac-1-mediated phagocytosis and the associated NADPH oxidase-generated ROS might have a dual role in inflammation. They have a well documented role in clearing microbial infections and might also promote resolution of the inflammatory response by triggering cell death of neutrophils that have reached the end of their useful life span. It is intriguing that molecules with seminal roles in inflammation also modulate cell apoptosis. Indeed, the connection between inflammation and cell
Acknowledgements
We gratefully acknowledge the contributions of current and previous members of our laboratories, and colleagues who have contributed to the results reviewed here. Due to space restrictions, it was not possible to cite all original references. This work was supported by the National Institutes of Health.
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