Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses Michael R. Elliott, Kyle M. Koster and Patrick S. Murphy This information is current as J Immunol 2017; 198:1387-1394; ; of September 25, 2021. doi: 10.4049/jimmunol.1601520 http://www.jimmunol.org/content/198/4/1387 Downloaded from References This article cites 126 articles, 38 of which you can access for free at: http://www.jimmunol.org/content/198/4/1387.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses Michael R. Elliott, Kyle M. Koster, and Patrick S. Murphy Since the pioneering work of Elie Metchnikoff and the modulate macrophage immune responses in the context of discovery of cellular immunity, the phagocytic clearance tissue inflammation. Although we primarily focus on mac- of cellular debris has been considered an integral com- rophage responses in this review, it is important to emphasize ponent of resolving inflammation and restoring func- that many different types of hematopoietic and nonhematopoietic tion of damaged and infected tissues. We now know cell types can carry out efferocytosis and that apoptotic cells that the phagocytic clearance of dying cells (efferocytosis), can exert important and sometimes cell type–specific im- particularly by macrophages and other immune phago- munoregulatory consequences on these phagocytes (reviewed cytes, has profound consequences on innate and adap- in Refs. 4–6). Downloaded from tive immune responses in inflamed tissues. These Cell death in inflamed tissues immunomodulatory effects result from an array of mo- Cell death is a universal feature of infected and damaged lecular signaling events between macrophages, dying tissues. Cell death can occur by unregulated, accidental means cells, and other tissue-resident cells. In recent years, such as mechanical or osmotic lysis, particularly in the early many of these molecular pathways have been identified stages of inflammation. However, inflammation-associated cell http://www.jimmunol.org/ and studied in the context of tissue inflammation, help- death can also result from the activation of specific biochemical ing us better understand the relationship between effer- pathways (e.g., apoptosis, necroptosis) (7). Apoptosis is the ocytosis and inflammation. We review specific types of most prominent mechanism of programmed cell death seen in efferocytosis-related signals that can impact macro- inflamed tissues for both hematopoietic and nonhematopoietic phage immune responses and discuss their relevance cells (1, 8). The stimuli that trigger apoptosis within inflamed to inflammation-related diseases. The Journal of Im- tissues vary widely depending on the type of inflammation, and munology, 2017, 198: 1387–1394. can be due to pathogen-derived, host-derived, or iatrogenic stimuli. However, it is important to note that inflammation- by guest on September 25, 2021 associated apoptosis is most often multifactorial, and in most issue injury or infection leads to the prompt activation inflammatory settings the precise cellular and molecular mecha- of a local inflammatory response to mediate pathogen nisms of apoptosis induction are poorly understood. Nonetheless, clearance and limit tissue damage. The proper ter- T it is clear that apoptotic cell death plays an integral role in the mination of this inflammatory cascade is important to allow outcome of tissue inflammation. execution of tissue repair and resolution responses required to Sepsis is one of the best-studied examples in which apoptosis restore normal tissue function. Improper resolution can result has clear and profound consequences on the resolution of in excessive scarring and organ damage as well as chronic inflammation. A life-threatening condition responsible for inflammation and loss of self-tolerance that contributes to ∼250,000 United States deaths annually, sepsis can occur disease states such as cardiovascular disease, cancer, and auto- when a localized infection fails to properly resolve, leading to immunity (1). In healthy, immune-competent hosts, most in- systemic inflammation, organ failure, and death (2, 3, 9). In flammatory episodes are self limiting, with endogenous host humans and mice, sepsis is associated with widespread apo- mechanisms successfully orchestrating the onset and resolution ptosis in lymphoid organs, causing dramatic reductions in of inflammation. The identification and molecular character- hematopoietic cell numbers, including thymic T cells, bone ization of these endogenous resolution pathways have been a marrow B cells, and peripheral lymphocytes (7, 10). This promising and intense area of research in recent years (1–3). In depletion can cause persistent lymphopenia that contributes this review, we will discuss how some of the signals that reg- to mortality (11). In mice, blockade of apoptosis using caspase ulate apoptotic cell clearance (efferocytosis) can also function to inhibitors or overexpression of antiapoptotic genes improves Department of Microbiology and Immunology, David H. Smith Center for Vaccine Immunology, University of Rochester School of Medicine and Dentistry, 601 Biology and Immunology, University of Rochester School of Medicine and Dentistry, Elmwood Avenue, Box 609, Rochester, NY 14642. E-mail address: michael_elliott@urmc. Rochester, NY 14642 rochester.edu Received for publication August 31, 2016. Accepted for publication September 23, Abbreviations used in this article: DC, dendritic cell; LAP, LC3-associated phagocytosis; 2016. lysoPC, lysophosphatidylcholine; NR, nuclear receptor; PtdSer, phosphatidylserine; S1P, sphingosine-1-phosphate; WT, wild-type. This work was supported by National Institutes of Health Grant R01 AI114554 (to M.R.E.) and in part by National Institutes of Health Grants T32 GM007356 Ó (to K.M.K.) and T32 GM007285 (to P.S.M.). Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Address correspondence and reprint requests to Dr. Michael R. Elliott, Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601520 1388 BRIEF REVIEWS: EFFEROCYTOSIS SIGNALING IN MACROPHAGE INFLAMMATION survival following polymicrobial sepsis (12, 13). Similarly, of uncleared apoptotic cells in situ along with spontaneous most myeloid cell populations are also depressed in sepsis inflammation and autoimmune disease (reviewed in Refs. 6, (e.g., monocytes, macrophages, dendritic cells [DC]), al- 26, 27). However, efferocytosis can also directly alter the in- though neutrophil survival is increased (14). Consequently, flammatory signaling pathways in the engulfing macrophage. sepsis-associated leukocyte apoptosis is thought to tran- In this review, we will discuss how many of the signals that siently impair immunity and contribute to the generation of mediate the three stages of efferocytosis also play important an immunosuppressed state known as compensatory anti- roles in driving the immunomodulatory effects of apoptotic inflammatory response syndrome (15). The extent to which cells on macrophages. immunomodulatory effects of efferocytosis contribute to sus- tained immune suppression is an important but poorly un- Find-me signaling in inflammation derstood area of sepsis research (16). For phagocytosis to occur, phagocytes must first find a cell Leukocyte apoptosis is also a characteristic feature of self- undergoing apoptosis. This find-me stage of efferocytosis is limiting inflammation resulting from acute, localized, and mediated by the release of numerous soluble factors that attract moderate injury or infection. However, unlike sepsis, apoptotic macrophages to the site of cell death (6, 28, 29). Key find-me cells are thought to be beneficial in self-resolving inflammation signals identified to date include triphosphate nucleotides by helping to reprogram tissue macrophages from a proin- (ATP, UTP) (30, 31), the chemokine CX3CL1 (32), and the flammatory to a proresolution state (17). Tissue-resident signaling lipids lysophosphatidylcholine (lysoPC) and sphingosine- macrophages are key immune sentinels and thus are among 1-phosphate (S1P) (33–35). Although all of these factors can Downloaded from the first immune cells to respond to tissue damage by pro- stimulate macrophage migration to apoptotic cells, the rele- ducing cytokines that initiate and orchestrate the recruitment vance of individual find-me signals in efferocytosis depends of granulocytes from the blood into the tissue (18). Neutro- on many factors, including phagocyte and apoptotic cell type phils typically accumulate in significant