Wound Macrophages as Key Regulators of Repair
2011; Elsevier BV; Volume: 178; Issue: 1 Linguagem: Inglês
10.1016/j.ajpath.2010.08.003
ISSN1525-2191
AutoresSamielle K. Brancato, Jorge E. Albina,
Tópico(s)Signaling Pathways in Disease
ResumoRecent results call for the reexamination of the phenotype of wound macrophages and their role in tissue repair. These results include the characterization of distinct circulating monocyte populations with temporally restricted capacities to migrate into wounds and the observation that the phenotype of macrophages isolated from murine wounds partially reflects those of their precursor monocytes, changes with time, and does not conform to current macrophage classifications. Moreover, findings in genetically modified mice lacking macrophages have confirmed that these cells are essential to normal wound healing because their depletion results in retarded and abnormal repair. This mini-review focuses on current knowledge of the phenotype of wound macrophages, their origin and fate, and the specific macrophage functions that underlie their reparative role in injured tissues, including the regulation of the cellular infiltration of the wound and the production of transforming growth factor-β and vascular endothelial growth factor. Recent results call for the reexamination of the phenotype of wound macrophages and their role in tissue repair. These results include the characterization of distinct circulating monocyte populations with temporally restricted capacities to migrate into wounds and the observation that the phenotype of macrophages isolated from murine wounds partially reflects those of their precursor monocytes, changes with time, and does not conform to current macrophage classifications. Moreover, findings in genetically modified mice lacking macrophages have confirmed that these cells are essential to normal wound healing because their depletion results in retarded and abnormal repair. This mini-review focuses on current knowledge of the phenotype of wound macrophages, their origin and fate, and the specific macrophage functions that underlie their reparative role in injured tissues, including the regulation of the cellular infiltration of the wound and the production of transforming growth factor-β and vascular endothelial growth factor. The resolution of injury through replacement by scar has been preserved in evolution and applies to virtually all soft tissues in mammals. A healed wound is the result of the activities of cells that constitute what can be conceptually described as a wound organ. This transient neoorgan is assembled at the time and site of injury and disassembled once repair is complete, leaving in place a scar as evidence of the repair process. The parenchyma of the wound organ is composed of a temporally changing assembly of inflammatory cells, neovessels, fibroblasts and myofibroblasts, regenerating nerves, and other cells specific to the site of the injury (eg, keratinocytes, osteocytes, and hepatocytes). Two recent developments led to this review of wound macrophages. First, studies in both humans and rodents have demonstrated the existence of diverse subpopulations of circulating monocytes with, at least in mice, distinct and time-restricted abilities to migrate into wounds and other sites of tissue injury (Figure 1). These immediate precursors of wound macrophages are required for repair by scarring in organs as diverse as skin, heart, liver, and kidney. Second, the concept that macrophages involved in tissue repair express the alternatively activated phenotype first proposed by Gordon1Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003; 3: 23-35Crossref PubMed Scopus (4721) Google Scholar has been retained in the literature.2Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6185) Google Scholar Results from studies of macrophages isolated from wounds, however, contest this paradigm by demonstrating that they are not alternatively activated. Wound macrophages exhibit phenotypes that partially reflect those of their monocyte precursors, change with time, and fail to be adequately described by macrophage classifications based on activation profiles or functional capacity (Figure 2).3Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google ScholarFigure 2Wound macrophage phenotypes. The figure depicts a simplified view of the polarization of macrophages toward classic and alternative activation phenotypes to illustrate the concept that wound macrophages share traits with both phenotypes. As discussed in the text, the phenotype of wound macrophages changes as the wound heals. This temporal variability is represented in the table by color-coded symbols indicating selected phenotypic traits of early versus late wound macrophages. Dash marks signify the phenotype marker is not expressed. Table cells are empty when there are no data to confirm or deny expression. Inducible nitric oxide synthase (iNOS) is expressed by macrophages in sterile rat wounds, in infected murine wounds, and in chronic and infected human wounds. Reactive oxygen species (ROS) are produced through the NADPH-dependent respiratory burst oxidase. Heparin-binding proteins (Ym1 and Ym2) are induced in alternatively activated murine macrophages during helminthic infections. Fizz1 (found in inflammatory zone 1) is also known as hypoxia-induced mitogenic factor or Relm-α. LPS, lipopolysaccharide; MR, mannose receptor-1.View Large Image Figure ViewerDownload (PPT) This review addresses the origin and fate of wound macrophages, their regulatory interactions with other cellular populations in the wound, and the roles of macrophage-derived transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) in the regulation of wound fibrosis and neovascularization, respectively. Wound macrophages, which derive mostly from circulating monocytes, are recruited to the site of injury. Monocytes rapidly acquire certain macrophage phenotypic traits on arrival at the wound (ie, mannose receptor-13Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google Scholar), while retaining others present in circulating cells (ie, Ly-6C and dectin-13Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google Scholar). Recent work has revealed the existence of at least two distinct monocyte subpopulations in mice.4Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1161) Google Scholar Inflammatory monocytes, characterized as Ly-6ChighCCR2highCX3CR1low, migrate into sites of inflammation, including wounds, during the early phase of the response to injury.3Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google Scholar, 5Nahrendorf M. Swirski F.K. Aikawa E. Stangenberg L. Wurdinger T. Figueiredo J.L. Libby P. Weissleder R. Pittet M.J. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.J Exp Med. 2007; 204: 3037-3047Crossref PubMed Scopus (1631) Google Scholar A second population of murine monocytes, defined as Ly-6ClowCCR2lowCX3CR1high and originally thought to be the precursors of tissue-resident macrophages,6Geissmann F. Jung S. Littman D.R. Blood monocytes consist of two principal subsets with distinct migratory properties.Immunity. 2003; 19: 71-82Abstract Full Text Full Text PDF PubMed Scopus (2582) Google Scholar egress the circulation into wounds and other sites of inflammation after the Ly-6ChighCCR2high CX3CR1low cells. CX3CR1 is expressed in murine skin wounds by infiltrating macrophages, myofibroblasts, and endothelial cells, and its ligand CX3CL1 (fractalkine) is found in wound macrophages and endothelial cells. Cutaneous wound healing is retarded in CX3CR1 knockout animals, where wounds exhibit reduced numbers of macrophages and myofibroblasts and decreased levels of TGF-β1 and VEGF.7Ishida Y. Gao J.L. Murphy P.M. Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function.J Immunol. 2008; 180: 569-579Crossref PubMed Scopus (220) Google Scholar The roles of CCR2 and CX3CR1 in the recruitment of monocytes into sites of inflammation in the mouse are not restricted to skin wounds. A study of experimental myocardial infarction in mice confirmed that both populations of monocytes migrate into the area of ischemic injury and, more importantly, that they do so in a temporally segregated fashion, with Ly-6ChighCCR2highCX3CR1low monocytes predominating during the first 3 days after coronary artery ligation and Ly-6ClowCCR2lowCX3CR1high cells increasing thereafter. Ly-6Chigh cells produce proinflammatory cytokines and require the engagement of CCR2 for recruitment into the ischemic lesion. The Ly-6ClowCCR2lowCX3CR1high macrophages release VEGF and are needed for collagen accumulation in the infarct.5Nahrendorf M. Swirski F.K. Aikawa E. Stangenberg L. Wurdinger T. Figueiredo J.L. Libby P. Weissleder R. Pittet M.J. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.J Exp Med. 2007; 204: 3037-3047Crossref PubMed Scopus (1631) Google Scholar The sequential infiltration by Ly-6Chigh and Ly-6Clow monocytes/macrophages was also found in the authors' laboratory in murine soft tissue wounds, along with evidence that wound macrophages isolated 1 day after wounding predominantly produce proinflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]), whereas those harvested from 7-day-old wounds release more TGF-β.3Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google Scholar Although Ly-6ClowCCR2lowCX3CR1high monocytes/macrophages are essential for the fibrotic response to infarction, elimination of the initial infiltrate of Ly-6ChighCCR2highCx3CR1low cells also results in decreased collagen deposition.5Nahrendorf M. Swirski F.K. Aikawa E. Stangenberg L. Wurdinger T. Figueiredo J.L. Libby P. Weissleder R. Pittet M.J. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions.J Exp Med. 2007; 204: 3037-3047Crossref PubMed Scopus (1631) Google Scholar It appears that Ly-6ChighCCR2high CX3CR1low cells set the stage for the repair of the injury by scarring. Supporting this view, the inactivation of CCR2 or CX3CR1 by either genetic or pharmacological means suppresses macrophage infiltration and the development of hepatic, renal, and pulmonary fibrosis in a variety of murine models.8Seki E. de Minicis S. Inokuchi S. Taura K. Miyai K. van Rooijen N. Schwabe R.F. Brenner D.A. CCR2 promotes hepatic fibrosis in mice.Hepatology. 2009; 50: 185-197Crossref PubMed Scopus (313) Google Scholar, 9Li L. Huang L. Sung S.S. Vergis A.L. Rosin D.L. Rose Jr, C.E. Lobo P.I. Okusa M.D. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury.Kidney Int. 2008; 74: 1526-1537Crossref PubMed Scopus (266) Google Scholar, 10Furuichi K. Gao J.L. Murphy P.M. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury.Am J Pathol. 2006; 169: 372-387Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 11Gharaee-Kermani M. McCullumsmith R.E. Charo I.F. Kunkel S.L. Phan S.H. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis.Cytokine. 2003; 24: 266-276Crossref PubMed Scopus (103) Google Scholar The expression of Ly-6C provides a useful marker to distinguish different populations of murine monocytes and macrophages. Its function in these cells remains unknown. Ly-6C belongs to a family of cell surface phosphatidylinositol-anchored glycoproteins expressed in varying degrees in leukocytes and some endothelial cells.12Gumley T.P. McKenzie I.F. Sandrin M.S. Tissue expression, structure and function of the murine Ly-6 family of molecules.Immunol Cell Biol. 1995; 73: 277-296Crossref PubMed Google Scholar No in vivo ligands for Ly-6 family members have been identified. Because these molecules lack transmembrane or intracellular domains, a variety of transduction mechanisms for Ly-6 have been proposed, including binding to intracellular Src tyrosine kinases through cytoskeletal proteins in cells of monocytic lineage.12Gumley T.P. McKenzie I.F. Sandrin M.S. Tissue expression, structure and function of the murine Ly-6 family of molecules.Immunol Cell Biol. 1995; 73: 277-296Crossref PubMed Google Scholar, 13Jaakkola I. Merinen M. Jalkanen S. Hanninen A. Ly6C induces clustering of LFA-1 (CD11a/CD18) and is involved in subtype-specific adhesion of CD8 T cells.J Immunol. 2003; 170: 1283-1290PubMed Google Scholar Antibody cross-linking of Ly-6C in CD8+ lymphocytes results in integrin activation and enhances adherence to endothelia.13Jaakkola I. Merinen M. Jalkanen S. Hanninen A. Ly6C induces clustering of LFA-1 (CD11a/CD18) and is involved in subtype-specific adhesion of CD8 T cells.J Immunol. 2003; 170: 1283-1290PubMed Google Scholar A similar function in monocytes could regulate their transvascular migration into wounds, but this possibility has not been reported. Although strong evidence supports the roles of CCR2/CCL2 and CX3CR1/CX3CL1 in the sequential recruitment of distinct macrophage precursors into wounds and other inflammatory lesions,7Ishida Y. Gao J.L. Murphy P.M. Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function.J Immunol. 2008; 180: 569-579Crossref PubMed Scopus (220) Google Scholar, 14Dipietro L.A. Reintjes M.G. Low Q.E. Levi B. Gamelli R.L. Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein-1.Wound Repair Regen. 2001; 9: 28-33Crossref PubMed Google Scholar it appears that a more complex signal network is required for the normal migration of monocytes into wounds. In this regard, an antiserum against CCL3 (macrophage inflammatory protein-1α, a chemokine that signals through chemokine receptors CCR1, 3, 5, and 9) decreased macrophage accumulation in wounds.15DiPietro L.A. Burdick M. Low Q.E. Kunkel S.L. Strieter R.M. MIP-1alpha as a critical macrophage chemoattractant in murine wound repair.J Clin Invest. 1998; 101: 1693-1698Crossref PubMed Scopus (240) Google Scholar In addition, a variety of genetic manipulations, including deletions of TNF-α receptor p55, β-1,4 galactosyltransferase, P/E selectin, or intercellular adhesion molecule-1, result in reduced recruitment of macrophages to wounds and, with the exception of the TNF-α receptor p55 knockouts, in impaired wound healing.16Eming S.A. Krieg T. Davidson J.M. Inflammation in wound repair: molecular and cellular mechanisms.J Invest Dermatol. 2007; 127: 514-525Crossref PubMed Scopus (1437) Google Scholar The relative roles of monocyte-derived and resident tissue macrophages (such as osteoclasts, pulmonary alveolar macrophages, microglia, and tissue histiocytes) in the repair of specific organs are not completely defined. However, there is evidence of cooperation between blood-derived and tissue macrophages in wound healing. For example, resident Kupffer cells participate in the fibrotic response to a variety of hepatic insults by secreting cytokines and growth factors and by activating hepatic stellate cells, but the extent of fibrosis is markedly reduced in CCR2 knockouts unable to recruit blood monocytes into the injured liver.8Seki E. de Minicis S. Inokuchi S. Taura K. Miyai K. van Rooijen N. Schwabe R.F. Brenner D.A. CCR2 promotes hepatic fibrosis in mice.Hepatology. 2009; 50: 185-197Crossref PubMed Scopus (313) Google Scholar Distinct populations of monocytes have also been described in humans, where they are distinguished by the expression of CD16.4Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1161) Google Scholar CD16+ cells, which normally constitute 5% to 15% of circulating monocytes, express high levels of CX3CR1 and may be the ortholog of Ly-6ClowCX3CR1high murine monocytes. The normally more abundant CD16− monocytes are CX3CR1low and resemble Ly-6Chigh murine monocytes in their expression of CCR2. A third population of human monocytes expressing both CD14 and CD16 has been shown to comprise at least 2 subpopulations with distinct capacities to release TNF-α and IL-1 in response to lipopolysaccharide. The function of these CD14+CD16+ cells remains unclear, but their frequency in the circulation increases in septic diseases.4Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1161) Google Scholar Whether human monocytes parallel their murine counterparts in their capacity to migrate into wounds in a temporally restricted manner and have differential secretory and functional profiles at a site of injury remains to be investigated. Macrophages disappear from wounds during the resolution of the inflammatory phase of repair. Some die at the wound, as evidenced by the appearance of intracellular macrophage molecules in the wound extracellular fluid (most notably macrophage arginase I in rat wounds).17Albina J.E. Mills C.D. Henry Jr, W.L. Caldwell M.D. Temporal expression of different pathways of 1-arginine metabolism in healing wounds.J Immunol. 1990; 144: 3877-3880PubMed Google Scholar Others are likely to migrate to draining lymph nodes. Although this possibility has not been reported specifically for wound macrophages, evidence provided by studies of the resolution of cellular infiltrates in other models of inflammation suggests its likelihood.18Bellingan G.J. Caldwell H. Howie S.E.M. Dransfield I. Haslett C. In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes.J Immunol. 1996; 157: 2577-2585PubMed Google Scholar, 19Harmsen A.G. Muggenburg B.A. Snipes M.B. Bice D.E. The role of macrophages in particle translocation from lungs to lymph nodes.Science. 1985; 230: 1277-1280Crossref PubMed Scopus (260) Google Scholar Whether these emigrating cells are true macrophages or monocyte-derived dendritic cells remains a topic in need of further investigation.20Randolph G.J. Inaba K. Robbiani D.F. Steinman R.M. Muller W.A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo.Immunity. 1999; 11: 753-761Abstract Full Text Full Text PDF PubMed Scopus (756) Google Scholar, 21Randolph G.J. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis.Curr Opin Lipidol. 2008; 19: 462-468Crossref PubMed Scopus (95) Google Scholar, 22Dominguez P.M. Ardavin C. Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation.Immunol Rev. 2010; 234: 90-104Crossref PubMed Scopus (203) Google Scholar The capacity of macrophages to exhibit a variety of phenotypic profiles in response to different stimuli has been used for their classification into distinct functional categories.23Stout R.D. Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments.J Leukoc Biol. 2004; 76: 509-513Crossref PubMed Scopus (546) Google Scholar In its most simplified version, the current paradigm holds that macrophages polarize either to a cytotoxic and microbicidal phenotype after stimulation with interferon-γ and lipopolysaccharide (the classically activated macrophage) or to an alternatively activated phenotype that is associated with parasitic infections and allergic reactions and induced by IL-4/IL-13.1Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003; 3: 23-35Crossref PubMed Scopus (4721) Google Scholar Because these extreme phenotypes are not expressed in pure form in vivo, recent publications have embraced the view that macrophage activation is best described by a continuous spectrum of phenotypic characteristics.2Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6185) Google Scholar The concept that wound macrophages express the alternatively activated phenotype has, however, been retained.2Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6185) Google Scholar, 24Lucas T. Waisman A. Ranjan R. Roes J. Krieg T. Muller W. Roers A. Eming S.A. Differential roles of macrophages in diverse phases of skin repair.J Immunol. 2010; 184: 3964-3977Crossref PubMed Scopus (754) Google Scholar Furthermore, it has been proposed that alternatively activated macrophages be reclassified as wound healing macrophages.2Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6185) Google Scholar This recommendation is not supported by studies of macrophages directly isolated from wounds. Findings from this laboratory in sterile murine wounds demonstrated that wound macrophages exhibit a mixed and temporally dependent phenotype with traits of both classically and alternatively activated cells and that neither IL-4 nor IL-13, the proposed determinants of the wound healing macrophage phenotype, are detectable in murine deep tissue wounds.3Daley J.M. Brancato S.K. Thomay A.A. Reichner J.S. Albina J.E. The phenotype of murine wound macrophages.J Leukoc Biol. 2010; 87: 59-67Crossref PubMed Scopus (325) Google Scholar The expression of the enzyme arginase by alternatively activated1Gordon S. Alternative activation of macrophages.Nat Rev Immunol. 2003; 3: 23-35Crossref PubMed Scopus (4721) Google Scholar or wound healing2Mosser D.M. Edwards J.P. Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969Crossref PubMed Scopus (6185) Google Scholar macrophages has been singled out as central to their putative role in tissue repair. Arginases catalyze the degradation of arginine to ornithine and urea. Ornithine can, in turn, be metabolized to proline, an amino acid that is abundant in collagens. The demonstration of extracellular arginase activity in rat wounds led this laboratory to propose that ornithine-derived proline could promote or facilitate collagen synthesis by increasing its availability to fibroblasts and myofibroblasts.17Albina J.E. Mills C.D. Henry Jr, W.L. Caldwell M.D. Temporal expression of different pathways of 1-arginine metabolism in healing wounds.J Immunol. 1990; 144: 3877-3880PubMed Google Scholar However, there is no direct evidence that native proline is limiting to collagen synthesis in wounds and, thus, that ornithine-derived proline is essential to repair. In fact, rat wound fibroblasts preferentially incorporate preformed, rather than ornithine-derived, proline into collagen.25Albina J.E. Abate J.A. Mastrofrancesco B. Role of ornithine as a proline precursor in healing wounds.J Surg Res. 1993; 55: 97-102Abstract Full Text PDF PubMed Scopus (92) Google Scholar Moreover, native proline suppresses the use of ornithine-derived proline during collagen synthesis by fibroblasts. Providing further evidence against arginase as a necessary regulator of collagen synthesis, a recent report demonstrated a paradoxical increase in fibrosis after infection with Schistosoma mansoni in animals with macrophage-specific deletion of arginase I.26Pesce J.T. Ramalingam T.R. Mentink-Kane M.M. Wilson M.S. El Kasmi K.C. Smith A.M. Thompson R.W. Cheever A.W. Murray P.J. Wynn T.A. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.PLoS Pathog. 2009; 5: e1000371Crossref PubMed Scopus (590) Google Scholar Most importantly, arginase I is not expressed in human monocytes or macrophages, even after polarization toward classic or alternatively activated phenotypes.27Munder M. Mollinedo F. Calafat J. Canchado J. Gil-Lamaignere C. Fuentes J.M. Luckner C. Doschko G. Soler G. Eichmann K. Muller F.M. Ho A.D. Goerner M. Modolell M. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity.Blood. 2005; 105: 2549-2556Crossref PubMed Scopus (248) Google Scholar, 28Raes G. Van den Bergh R. De Baetselier P. Ghassabeh G.H. Scotton C. Locati M. Mantovani A. Sozzani S. Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells.J Immunol. 2005; 174: 6561PubMed Google Scholar Contrasting the macrophage-restricted expression of arginase I in rodent wounds,17Albina J.E. Mills C.D. Henry Jr, W.L. Caldwell M.D. Temporal expression of different pathways of 1-arginine metabolism in healing wounds.J Immunol. 1990; 144: 3877-3880PubMed Google Scholar arginase has been found in neutrophils in acute human wounds and in fibroblasts in chronic wounds and ulcers but not in macrophages.29Debats I.B. Wolfs T.G. Gotoh T. Cleutjens J.P. Peutz-Kootstra C.J. van der Hulst R.R. Role of arginine in superficial wound healing in man.Nitric Oxide. 2009; 21: 175-183Crossref PubMed Scopus (82) Google Scholar, 30Jude E.B. Boulton A.J. Ferguson M.W. Appleton I. The role of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: possible modulatory effects by transforming growth factor beta 1.Diabetologia. 1999; 42: 748-757Crossref PubMed Scopus (109) Google Scholar Arginase I is also expressed in human, but not in rodent, erythrocytes,31Spector E.B. Rice S.C. Kern R.M. Hendrickson R. Cederbaum S.D. Comparison of arginase activity in red blood cells of lower mammals, primates, and man: evolution to high activity in primates.Am J Hum Genet. 1985; 37: 1138-1145PubMed Google Scholar and lysed red blood cells contribute arginase to human wounds. Arginase activity is highest in postmastectomy wound fluids within 24 hours of surgery and correlates with the hemoglobin concentration in the fluids (unpublished observations). The potential role of mammalian red blood cell arginase I in early inflammation and repair has not been identified. Arginase expression by wound macrophages is, thus, species restricted and probably not essential for normal collagen deposition in wounds. Macrophages control the cellularity of wounds through their capacity to induce apoptosis and phagocytose a variety of wound cells. Macrophage-targeted cells include neutrophils during the inflammatory phase of repair and fibroblasts and endothelial cells during its resolution. Tissue injury is followed by the sequential infiltration of the wound by neutrophils and macrophages. The number of neutrophils decreases as the wound matures and macrophages become the predominant inflammatory cell. Neutrophils undergo apoptosis in the wound and are recognized and ingested by macrophages.32Metchnikoff E. Leçons sur la pathologie comparée de l'inflammation. Masson, Paris1892Google Scholar, 33Meszaros A.J. Reichner J.S. Albina J.E. Macrophage phagocytosis of wound neutrophils.J Leukoc Biol. 1999; 65: 35-42PubMed Google Scholar In addition, rat wound macrophages actively induce apoptosis in neutrophils.34Meszaros A.J. Reichner J.S. Albina J.E. Macrophage-induced neutrophil apoptosis.J Immunol. 2000; 165: 435-441PubMed Scopus (83) Google Scholar The induction of neutrophil apoptosis requires the expression of membrane-bound TNF-α (but not soluble TNF-α), β3-integrins, and CD36 by the effector macrophages. Neither resident nor Propionibacterium acnes–elicited peritoneal macrophages induced apoptosis in neutrophils, indicating this ability to be particular to wound macrophages.34Meszaros A.J. Reichner J.S. Albina J.E. Macrophage-induced neutrophil apoptosis.J Immunol. 2000; 165: 435-441PubMed Scopus (83) Google Scholar The phagocytosis of apoptotic neutrophils or other cells has been shown to induce an anti-inflammatory phenotype in macrophages. This phenotype includes the release of TGF-β and prostaglandin E2 and a reduced ability to produce proinflammatory mediators, such as TNF-α, after lipopolysaccharide stimulation.35Savill J. Fadok V. Corpse clearance defines the meaning of cell death.Nature. 2000; 407: 784-788Crossref PubMed Scopus (1273) Google Scholar Because Ly-6Chigh wound macrophages produce TNF-α and Ly-6Clow murine monocytes are more efficient than Ly-6Chigh cells in the ingestion of apoptotic cells,36Peng Y. Latchman Y. Elkon K.B. Ly6C(low) monocytes differentiate into dendritic cells and cross-tolerize T cells through PDL-1.J Immunol. 2009; 182: 2777-2785Crossref PubMed Scopus (41) Google Scholar it appears reasonable to propose that Ly-6Chigh cells induce apoptosis in wound neutrophils, whereas Ly-6Clow cells remove postapoptotic debris from the wound space. Studies in CD18 knockout mice that model for leukocyte adhesion deficiency syndrome 1, a disorder characterized by recurrent infections and impaired wound healing in humans, have provided further information regarding macrophage/neutrophil interactions in wounds.37Peters T. Sindrilaru A. Hinz B. Hinrichs R. Menke A. Al-Azzeh E.A. Holzwarth K. Oreshkova T. Wang H. Kess D. Walzog B. Sulyok S. Sunderkotter C. Friedrich W. Wlaschek M. Krieg T. Scharffetter-Kochanek K. Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.EMBO J. 2005; 24: 3400-341
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