Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing Anna E. Boniakowski, Andrew S. Kimball, Benjamin N. Jacobs, Steven L. Kunkel and Katherine A. Gallagher This information is current as of October 1, 2021. J Immunol 2017; 199:17-24; ; doi: 10.4049/jimmunol.1700223 http://www.jimmunol.org/content/199/1/17 Downloaded from References This article cites 108 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/199/1/17.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 October 1, 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 Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing Anna E. Boniakowski,* Andrew S. Kimball,† Benjamin N. Jacobs,† Steven L. Kunkel,‡ and Katherine A. Gallagher* The healing of cutaneous wounds is dependent on the pro- MF plasticity is crucial for wound repair. In this review, we gression through distinct, yet overlapping phases of wound will consider how MFs in the wound regulate inflammation healing, including hemostasis, inflammation, proliferation, and tissue repair. Comparatively, we will examine a patho- and resolution/remodeling. The failure of these phases to logic setting where loss of MF plasticity can lead to dysreg- occur in a timely, progressive fashion promotes pathologic ulated inflammation and impaired wound healing. wound healing. The macrophage (MF) has been demon- MFs and wound healing strated to play a critical role in the inflammatory phase of Downloaded from tissue repair, where its dynamic plasticity allows this cell Wound healing is exceedingly complex, and it represents the to mediate both tissue-destructive and -reparative func- evolutionary layering of numerous genetic, epigenetic, and tions. The ability to understand and control both the molecular processes to accomplish this goal. The process of initiation and the resolution of inflammation is critical human tissue repair is tightly regulated, and it proceeds in an for treating pathologic wound healing. There are now a orderly manner under normal conditions. This stepwise, regular host of studies demonstrating that metabolic and epige- order in which tissue healing takes place is divided into four http://www.jimmunol.org/ netic regulation of gene transcription can influence MF stages, corresponding roughly to the four waves of predominant plasticity in wounds. In this review, we highlight the cell type appearing in the wound bed (1). These are the he- molecular and epigenetic factors that influence MF po- mostasis, inflammatory, proliferative, and maturation phases. larization in both physiologic and pathologic wound heal- In the hemostasis phase, platelets and circulating coagulant ing, with particular attention to diabetic wounds. The factors accumulate at the site of tissue injury. The interactions Journal of Immunology, 2017, 199: 17–24. of these factors, along with activation of the endothelium, promote the initial invasion of immune cells, specifically polymorphonuclear leukocytes (PMNs). The arrival of these by guest on October 1, 2021 aintenance of skin integrity is crucial to survival, cells characterizes the beginning of the inflammatory phase (2). and tissue repair is an elaborate process that must This rapid, initial influx of PMNs is followed by successive M be tightly regulated. Although many cell types are waves of infiltrating monocytes that differentiate within the involved in tissue repair, the macrophage (MF) has been wound into MFs and dendritic cells. As injured tissue demonstrated to play a critical regulatory role in the healing progresses through the inflammatory phase, the predominant process, particularly during the inflammatory phase of heal- MF phenotype in the wound bed changes as well. These ing. MFs represent a phenotypically heterogeneous set of changing populations result from successive waves of circu- innate immune cells, demonstrating a broad range of func- lating monocyte invasion, as well as changes in the local tissue tions in both health and disease. Notably, the MF is active environment that direct the phenotypic expression in the in both the initiation and the resolution of inflammatory tissue-resident MF (trMF) (3–5). Through this plasticity, processes. Early in wound repair, transcriptional changes in MFs both direct inflammation and tissue destruction and MFs lead to production of inflammatory cytokines and promote tissue repair and transition to the proliferative phase clearance of pathogens and debris. During later stages of the of healing. After resolution of the inflammatory phase, the inflammatory phase of wound healing, MFs contribute to the proliferative phase ensues, in which fibroblasts and other cells resolution of inflammation and promote tissue repair. It is reconstitute the tissue matrix, via deposition of collagens, this paradox—that the MF exists both to promote tissue primarily type III early and type I later as healing progresses destruction and later repair—that makes the MF one of the (6, 7). Contractile myofibroblasts contribute to wound con- most fascinating and important cells in the wound-healing traction (8). The final phase of healing is the maturation or process. remodeling phase, where the extracellular matrix expands and *Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Abbreviations used in this article: ATM, adipocyte tissue MF; HDAC, histone deace- Arbor, MI 48109; †Section of General Surgery, Department of Surgery, University of tylase; H3K, histone H3 lysine; IRF, IFN-regulatory factor; MF, macrophage; M1, Michigan, Ann Arbor, MI 48109; and ‡Department of Pathology, University of Mich- proinflammatory MoMF; M2, anti-inflammatory MoMF; MMP, matrix metallopro- igan, Ann Arbor, MI 48109 teinase; MoMF, monocyte-MF; PMN, polymorphonuclear leukocyte; SIRT, sirtuin; T2D, type 2 diabetes; trMF, tissue-resident MF. Received for publication February 13, 2017. Accepted for publication April 20, 2017. Address correspondence and reprint requests to Dr. Katherine A. Gallagher, Section of Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Vascular Surgery, University of Michigan, 1500 East Medical Center Drive, SPC 5867, Ann Arbor, MI 48109. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700223 18 BRIEF REVIEWS: MACROPHAGE-MEDIATED INFLAMMATION IN WOUND HEALING tissue strength returns, although ultimately reaching only 70% it has been well demonstrated that trMFs and MoMFsarein of its initial strength (7). fact quite different in gene transcription and in their function Recently, there has been a significant focus on the charac- within the wound bed (20, 21). These are, in fact, indepen- terization of the various expressions of in vivo MF phenotypes. dently maintained populations during wound inflammation Consistent identification of monocyte-MF (MoMF) sub- and subsequent resolution. The origins of these two pop- types in vitro and in vivo has been controversial in the liter- ulations differ: trMFs are, with the exception of those in the ature because of poor consensus on nomenclature and cell gastrointestinal tract, of embryonic origin, originating in the marker definitions (9). For example, NOS2 has traditionally fetal liver and on embryonic day 9 in the yolk sac and seeding been used to identify proinflammatory MoMFs by immu- cutaneous and organ tissues early in mammalian development nohistochemistry, whereas Arg-1 has been used to identify (22–25). In contrast, MoMFs are hematopoietic cells of the anti-inflammatory MoMFs (10). These definitions are prob- myeloid lineage (22–25). trMFs are thought to have tissue- lematic, however, because Arg-1 is also expressed in both specific roles in the healing process (26) and are, along with proinflammatory MoMFsandsometrMFs(11).Othermarkers mast cells, dendritic cells, and stromal cells, activated in the have been suggested in defining these MoMF populations, for immediate phase of injury by a number of cellular damage example, CCR2 for proinflammatory MoMFsandCD163or signals. These damage signals are released by direct cellular CD206 (mannose receptor) for anti-inflammatory MoMFs, all injury, pathogen entry, or toxic and oxidative stressors (27). with varying success (10). For example, alarmins, a diverse group of molecules that play MF phenotype identification, particularly in vivo, has a variety of intracellular roles in the steady-state, are released remained elusive, because wound MFscoexpressthesame upon injury into the extracellular milieu, where they activate Downloaded from markers across subtypes and alter their surface marker ex- local inflammatory cells through pattern recognition receptors pression profile in subtly different environments.