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• W4242171500 abstract "Nonresolving inflammation is a major driver of disease. Perpetuation of inflammation is an inherent risk because inflammation can damage tissue and necrosis can provoke inflammation. Nonetheless, multiple mechanisms normally ensure resolution. Cells like macrophages switch phenotypes, secreted molecules like reactive oxygen intermediates switch impact from pro- to anti-inflammatory, and additional mediators of resolution arise, including proteins, lipids, and gasses. Aside from persistence of initiating stimuli, nonresolution may result from deficiencies in these mechanisms when an inflammatory response begins either excessively or subnormally. This greatly complicates the development of anti-inflammatory therapies. The problem calls for conceptual, organizational, and statistical innovations. Nonresolving inflammation is a major driver of disease. Perpetuation of inflammation is an inherent risk because inflammation can damage tissue and necrosis can provoke inflammation. Nonetheless, multiple mechanisms normally ensure resolution. Cells like macrophages switch phenotypes, secreted molecules like reactive oxygen intermediates switch impact from pro- to anti-inflammatory, and additional mediators of resolution arise, including proteins, lipids, and gasses. Aside from persistence of initiating stimuli, nonresolution may result from deficiencies in these mechanisms when an inflammatory response begins either excessively or subnormally. This greatly complicates the development of anti-inflammatory therapies. The problem calls for conceptual, organizational, and statistical innovations. Inflammation is a frequent occurrence because we are partly microbial and we move in a microbial world. These circumstances ensure countless encounters with microbial stimuli in the context of tissue injury. The conjunction of these two types of stimuli in time and space is what most often initiates inflammation (Nathan, 2002Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2010) Google Scholar). The usual result of inflammation is protection from the spread of infection, followed by resolution—the restoration of affected tissues to their normal structural and functional state. The problem with inflammation is not how often it starts, but how often it fails to subside. Perhaps no single phenomenon contributes more to the medical burden in industrialized societies than nonresolving inflammation. Nonresolving inflammation is not a primary cause of atherosclerosis, obesity, cancer, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, neurodegenerative disease, multiple sclerosis, or rheumatoid arthritis, but it contributes significantly to their pathogenesis. This illustrative but noncomprehensive review begins by describing different forms of nonresolving inflammation. We then discuss damage of uninfected tissues as a propagator of inflammation. This is a critical conceptual issue, because microbial stimuli are not implicated in many forms of chronic inflammation, and it is instructive to appreciate the adaptive value of our ability to launch a tissue-damaging process triggered by tissue damage itself. Next, we ask two questions interchangeably that mirror each other: How does inflammation resolve? How can resolution fail? Given that the answers are complex and incomplete, we close by considering implications for the future of anti-inflammatory therapy. Nonresolving inflammation can take distinct histologic forms, as illustrated in Figure 1. These can succeed each other or coexist in different sites in an affected organ. Inflammation sometimes progresses from acute to chronic and then stalls for a prolonged period, although signs of acute inflammation, such as accumulation of neutrophils, may reappear later. Classic examples involve persistent infections. The contribution of inflammation to pathogenesis deserves emphasis when the host inflammatory response, not toxins from the pathogen, is chiefly responsible for the damage to the host. Globally, tuberculosis is probably the most prevalent example. Chronic inflammation surrounding Mycobacterium tuberculosis can persist for decades. When the inflammation is extensive enough, it liquefies lung. The host suffers loss of respiratory capacity and sometimes blood; the pathogen gets a ride on infectious droplets to enter another host. An enormous proportion of the global burden of disease involves nonresolving inflammation that appears to be chronic from the outset, in that the first cellular signs of inflammation involve infiltration of the tissue by monocytes, dendritic cells, and macrophages. Examples include atherosclerosis (Galkina and Ley, 2009Galkina E. Ley K. Immune and inflammatory mechanisms of atherosclerosis (∗).Annu. Rev. Immunol. 2009; 27: 165-197Crossref PubMed Scopus (1128) Google Scholar), obesity (Nathan, 2008Nathan C. Epidemic inflammation: pondering obesity.Mol. Med. 2008; 14: 485-492PubMed Google Scholar), and some cancers (Mantovani et al., 2008Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation.Nature. 2008; 454: 436-444Crossref PubMed Scopus (7861) Google Scholar). Frequently, acute and chronic inflammation coexist over long periods, implying continual reinitiation. Examples are found in rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, multiple sclerosis, Crohn's disease, ulcerative colitis, and cancers whose stroma is infiltrated both by macrophages and immature myeloid cells (Mantovani et al., 2008Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation.Nature. 2008; 454: 436-444Crossref PubMed Scopus (7861) Google Scholar). For example, in rheumatoid arthritis, the synovium presents a striking picture of chronic inflammation, with extensive infiltration by macrophages and lymphocytes and activation of synoviocytes. In contrast, the synovial fluid is a sea of neutrophils. The effusion in an affected joint of an untreated patient with rheumatoid arthritis can be invaded by over a billion neutrophils per day that have a half-life of about 4 hr (Hollingsworth et al., 1967Hollingsworth J.W. Siegel E.R. Creasey W.A. Granulocyte survival in synovial exudate of patients with rheumatoid arthritis and other inflammatory joint diseases.Yale J. Biol. Med. 1967; 39: 289-296PubMed Google Scholar). Neutrophils contain cytosolic peptidyl arginine deiminase type 4, an enzyme whose activity depends on the levels of Ca2+ found in extracellular fluid. When neutrophils die, this enzyme may be released and activated. It may then convert the guanidino side chains of L-arginine residues to ureido residues, generating citrulline in some proteins in the joint. The autoantibodies most closely associated with the pathogenesis of rheumatoid arthritis react with citrullinated proteins (Uysal et al., 2009Uysal H. Bockermann R. Nandakumar K.S. Sehnert B. Bajtner E. Engström A. Serre G. Burkhardt H. Thunnissen M.M. Holmdahl R. Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.J. Exp. Med. 2009; 206: 449-462Crossref PubMed Scopus (188) Google Scholar). Thus, dying neutrophils may help sustain an ongoing antigen-antibody reaction that attracts and activates more neutrophils, whose secretion of oxidants and proteases is synergistically destructive (Han et al., 2005Han H. Stessin A. Roberts J. Hess K. Gautam N. Kamenetsky M. Lou O. Hyde E. Nathan N. Muller W.A. et al.Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils.J. Exp. Med. 2005; 202: 353-361Crossref PubMed Scopus (57) Google Scholar). Successful postinflammatory tissue repair requires the coordinated restitution of different cell types and structures, not only epithelial and mesenchymal cells but also extracellular matrix and vasculature. Chemokines are critical to vascular remodeling after inflammation (Strieter et al., 2007Strieter R.M. Gomperts B.N. Keane M.P. The role of CXC chemokines in pulmonary fibrosis.J. Clin. Invest. 2007; 117: 549-556Crossref PubMed Scopus (215) Google Scholar). Without appropriate restitution of vasculature, altered tissue oxygenation may preclude normal repair, resulting in atrophy or fibrosis. When these processes destroy an organ, we do not know how to restore normal function short of replacing the organ by transplantation. Atrophy refers to the loss of parenchymal cells. For example, atrophy of the stomach follows longstanding inflammation caused by infection with Helicobacter pylori, resulting in loss of mucosal function and failure to produce gastric acid. Atrophy is often accompanied by expansion of extracellular tissue elements, particularly collagen, resulting in fibrosis, the deposition of excess connective tissue. It is likely that atrophy sometimes promotes fibrosis, fibrosis sometimes promotes atrophy, and each can occur independently. Both can arise without known preceding inflammation. Fibrosis sufficient to interfere with organ function is a major medical problem after inflammation of arteries caused by accumulation of cholesterol, inflammation of the liver caused by viruses, alcohol, toxins or schistosome infections, inflammation of the lung associated with asthma or radiotherapy, and inflammation of the bowel in Crohn's disease, where fibrotic strictures (occlusions) often require surgery. Fibrosis arises from the excessive number, activity, or life span of collagen producing cells—activated fibroblasts, epithelial cells that undergo transformation to a mesenchymal phenotype, hepatic stellate cells that generate myofibroblasts, and bone marrow-derived fibrocytes that enter an affected organ from the circulation. Various chemokines attract fibrocytes into an inflammatory site, where TGF-β promotes their differentiation (Abe et al., 2001Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J. Immunol. 2001; 166: 7556-7562PubMed Google Scholar, Strieter et al., 2007Strieter R.M. Gomperts B.N. Keane M.P. The role of CXC chemokines in pulmonary fibrosis.J. Clin. Invest. 2007; 117: 549-556Crossref PubMed Scopus (215) Google Scholar). Also important are the factors governing the apoptosis of collagen-producing cells during the resolution of inflammation. TLR agonists can activate fibroblasts directly (Wynn, 2008Wynn T.A. Cellular and molecular mechanisms of fibrosis.J. Pathol. 2008; 214: 199-210Crossref PubMed Scopus (3062) Google Scholar). Cytokines with a prominent role in promoting fibrosis include TGF-β, IL-13, IL-4, IL-6, and IL-21. Directly or through their influence on chemokine expression, these cytokines can recruit and augment the proliferation of fibrocytes, fibroblasts, and myofibroblasts and promote their production of collagen (Wilson and Wynn, 2009Wilson M.S. Wynn T.A. Pulmonary fibrosis: pathogenesis, etiology and regulation.Mucosal Immunol. 2009; 2: 103-121Crossref PubMed Scopus (513) Google Scholar, Wynn, 2008Wynn T.A. Cellular and molecular mechanisms of fibrosis.J. Pathol. 2008; 214: 199-210Crossref PubMed Scopus (3062) Google Scholar). IL-4 induces macrophages to express TGF-β, PDGF, and arginase. Ornithine, a product of arginase, is a significant source of the proline and hydroxyproline that together account for almost a quarter of the residues in collagen. TGF-β activity is post-translationally regulated by release from latency-associated protein, often by proteolysis. For this and additional reasons, the balance between proteases and antiproteases (which in turn is critically regulated by reactive oxygen intermediates, or ROI) may play a large role in the degree of fibrosis that follows inflammation. TGF-β induces mesenchymal cells to express NADPH oxidase 4 (NOX4), whose production of ROI mediates TGF-β-dependent myofibroblast differentiation and extracellular matrix production (Hecker et al., 2009Hecker L. Vittal R. Jones T. Jagirdar R. Luckhardt T.R. Horowitz J.C. Pennathur S. Martinez F.J. Thannickal V.J. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury.Nat. Med. 2009; 15: 1077-1081Crossref PubMed Scopus (639) Google Scholar). IL-13 promotes both the production of TGF-β by macrophages and its proteolytic activation, although IL-13 can also promote fibrosis independently of the TGF-β/Smad signaling pathway (Wynn, 2008Wynn T.A. Cellular and molecular mechanisms of fibrosis.J. Pathol. 2008; 214: 199-210Crossref PubMed Scopus (3062) Google Scholar). Macrophage- and fibroblast-derived angiotensin II is another profibrotic stimulus that works at least in part through augmentation of TGF-β production (Wynn, 2008Wynn T.A. Cellular and molecular mechanisms of fibrosis.J. Pathol. 2008; 214: 199-210Crossref PubMed Scopus (3062) Google Scholar). Bioactivity of TGF-β is further controlled by the expression of matrix proteins that bind it in an inactive state. Endogenous antagonists of fibrosis include IFN-γ, IL-12, IL-10, and IL-13αR2, a decoy receptor (Wynn, 2008Wynn T.A. Cellular and molecular mechanisms of fibrosis.J. Pathol. 2008; 214: 199-210Crossref PubMed Scopus (3062) Google Scholar). Shared actions of IFN-γ and IL-10 are uncommon, and it will be fruitful to learn more about how each of them suppresses fibrosis. In sum, tissue healing has features in common with tissue development, which requires involution of pre-existing tissue elements. However, distinct challenges arise when the pre-existing tissue has been damaged and inflamed. It is not just the expression or extinction of certain mediators that is critical, but the orchestration of their succession—that is, their tuning and timing. As hinted above, inflammation can reduce any site in the body to a liquid that contains few living cells or intact macromolecules, or harden it into a mass packed with infiltrating lymphohematopoietic cells or stiffened by collagen. What if tissue damage, in turn, were to trigger inflammation? Wouldn't that set up a positive feedback loop that could send us all to an early grave? By itself, sterile tissue injury, as generated by well-performed surgery, provokes little or no clinically apparent inflammation. Fortunately, since we are human-microbial consortia, the presence of microbial products in the absence of tissue injury is noninflammatory as well. As mentioned, it is when signals arising from tissue injury coincide with signals arising from microbes that inflammation usually ensues (Nathan, 2002Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2010) Google Scholar). Nonetheless, inflammation does arise when large numbers of host cells die in place, such as in a heart attack or stroke. Although inflammation in such settings usually resolves quickly, it often contributes to the damage precipitated by the underlying event. Why have we evolved to allow noninfectious cell death to trigger a response that exacerbates noninfectious cell death? An evolutionary perspective suggests an explanation, as summarized in Figure 2. The host senses microbial products in two ways: directly, via host molecules that bind microbial products, and indirectly, by host molecules that detect products of host cell necrosis. Microbial products can reach host detectors in two ways: by direct contamination of tissues, such as via cuts, bites or burns, or by diffusion of secreted, shed, or released microbial products through extracellular fluid, lymph, or blood. The host needs to be particularly vigilant in detecting microbial toxins that diffuse or circulate because toxins can allow a tiny bacterial biomass to incapacitate a vastly larger host. Relying on a receptor to detect a toxin may provide less warning than relying on multiple receptors to detect the damage the toxin causes. Making an advantage of necessity, the host uses necrosis of its cells as one of the immune system's earliest and best-amplified signals to report the dissemination of a microbial toxin. In evolution, sterile surgical technique was unknown, ischemic events like heart attacks and strokes—largely afflictions of the elderly—would not have imposed large selective pressures, and most cases of tissue injury that exerted large selective pressures in individuals with reproductive potential were contaminated by or caused by microbes. Thus, it is plausible that animals have evolved to interpret necrotic host cells as a sign of infection. The molecular signals of host cell necrosis that trigger inflammation are still being defined and debated (Kono and Rock, 2008Kono H. Rock K.L. How dying cells alert the immune system to danger.Nat. Rev. Immunol. 2008; 8: 279-289Crossref PubMed Scopus (1292) Google Scholar), but they are many and diverse. Examples include uric acid, adenosine, oxidized 1-palmitoyl-2-arachidonyl-phosphatidylcholine (Imai et al., 2008Imai Y. Kuba K. Neely G.G. Yaghubian-Malhami R. Perkmann T. van Loo G. Ermolaeva M. Veldhuizen R. Leung Y.H. Wang H. et al.Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.Cell. 2008; 133: 235-249Abstract Full Text Full Text PDF PubMed Scopus (1052) Google Scholar), chromosomal DNA (Okabe et al., 2009Okabe Y. Sano T. Nagata S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent.Nature. 2009; 460: 520-524PubMed Google Scholar), IL-1α, IL-33, high-mobility group box-1 (HMGB1), nonmuscle myosin recognized by complement-fixing antibodies present in normal mice (Zhang et al., 2006Zhang M. Alicot E.M. Chiu I. Li J. Verna N. Vorup-Jensen T. Kessler B. Shimaoka M. Chan R. Friend D. et al.Identification of the target self-antigens in reperfusion injury.J. Exp. Med. 2006; 203: 141-152Crossref PubMed Scopus (194) Google Scholar), and fragments of extracellular matrix proteins generated by release of proteases from dying cells (Kono and Rock, 2008Kono H. Rock K.L. How dying cells alert the immune system to danger.Nat. Rev. Immunol. 2008; 8: 279-289Crossref PubMed Scopus (1292) Google Scholar). Reflecting the extremely close relationship between detection of microbial products and detection of host cell injury, many, perhaps most, of the host molecules that specifically recognize microbial products also recognize one or another host product whose formation or relocalization reports host cell necrosis. This sets the stage to consider mechanisms that drive the resolution of inflammation and how they may sometimes fail, as summarized in Figure 3. We avoid spontaneous inflammation through a set of tonically operating anti-inflammatory mechanisms. This was inferred from the phenotype resulting from loss-of-function mutations in what were earlier counted as over 50 genes (Nathan, 2002Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2010) Google Scholar), and are now recognized as at least 81 (Table 1; for abbreviations and references, see Table S1 available online). These mutations lead to spontaneous emergence of persistent inflammation in people living in normal conditions or in laboratory mice during standard husbandry—that is, without a known inflammatory provocation, and without evident autoimmunity. Apparently, it takes a complex, coordinated response by 81 or more gene products to prevent inflammation from arising spontaneously. The true number is likely to be higher, given what this list implies: that spontaneous inflammation may arise whenever we lose a nonredundant component of a mechanism that regulates proliferation or signaling in lymphoid, myeloid, or epithelial cells responding to antigens, microbes, or injury.Table 1Gene Products Required to Maintain Basal Anti-inflammatory ToneFunctional ClassGene ProductRegulation of Apoptosis and Clearance of Apoptotic CellsFas, Fas, C1q, C1q, C2, C4, C4, C3, C4 BP, factor H, Crry, SAP, DNAse I, DNAse II, FcγRIIB, WASP, WASP, c-mer, caspase 8, TIPE2Cytokines and Cell Surface ReceptorsTNFR1, TNFR1, TGF-β1, IL-2Rα, IL-2, IL-10, IL-10R, GM-CSF, GM-CSF, IL-1Ra, IL-1Ra, TcRα, TcR β, MHCII, CTLA4, PD1, TAC1, aEβ7 (CD103), αv integrinOther Membrane or Intracellular Proteins of Lymphocytes, Leukocytes, or Epithelial Cells Affecting Their ActivationZAP70, MDR1α, LAT, TSAd, SOCS1, PI3K p110δ, PTEN, lyn, cbl-b, Gαi2, SHP-1, SHIP, p21, TIA-1, tristetraproline, A20, NFAT, IKK-2, IKKγ, IKKγ, IκBα, IκBα, Rel-b, NF-κB1, Ndfip1, T-bet, Gadd45a, IRF-2, RabGEF1, NOD2/CARD15, pyrin, cryopyrin, mevalonate kinase, Foxj1, Foxo3a, p120-catenin, RXRα/β, JunB/cJun, TRAF6, CAT2, PSTPIP1, PSTPIP2, α-mannosidase-II, RUNX3, SH3BP2, TAK1, XBP1OtherHeme oxygenase 1, surfactant protein D, STAMP2, miR-223Proteins encoded by genes whose mutation leads to spontaneous inflammatory states not attributable to infection or autoimmunity. Human products are underlined; others are mouse. For abbreviations and references, see Table S1. This table is updated from Nathan, 2002Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2010) Google Scholar. Open table in a new tab Proteins encoded by genes whose mutation leads to spontaneous inflammatory states not attributable to infection or autoimmunity. Human products are underlined; others are mouse. For abbreviations and references, see Table S1. This table is updated from Nathan, 2002Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2010) Google Scholar. Examples involving those three cell types are instructive. TNF-α-induced protein-2 (TIPE2) is selectively expressed in lymphoid cells and acts to dampen signals from the T cell receptor and TLRs (Sun et al., 2008Sun H. Gong S. Carmody R.J. Hilliard A. Li L. Sun J. Kong L. Xu L. Hilliard B. Hu S. et al.TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis.Cell. 2008; 133: 415-426Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Mice that lacked TIPE2 died from accumulation of lymphocytes and macrophages in their lungs, liver, and intestines and of inflammatory cytokines in their blood (Sun et al., 2008Sun H. Gong S. Carmody R.J. Hilliard A. Li L. Sun J. Kong L. Xu L. Hilliard B. Hu S. et al.TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis.Cell. 2008; 133: 415-426Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Similarly, loss of function of a myeloid-specific microRNA led to overproliferation and hyperactivity of granulocytes and to spontaneous development of interstitial pneumonitis (Johnnidis et al., 2008Johnnidis J.B. Harris M.H. Wheeler R.T. Stehling-Sun S. Lam M.H. Kirak O. Brummelkamp T.R. Fleming M.D. Camargo F.D. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.Nature. 2008; 451: 1125-1129Crossref PubMed Scopus (988) Google Scholar). When oxidation or mistranslation of proteins leads to their unfolding, the endoplasmic reticulum membrane-spanning enzyme IRE1 activates a transcription factor, X box binding protein 1. Mice in which XBP1 was selectively deleted from intestinal epithelial cells developed neutrophilic accumulations in their small intestines, along with abscesses and ulcers (Kaser et al., 2008Kaser A. Lee A.H. Franke A. Glickman J.N. Zeissig S. Tilg H. Nieuwenhuis E.E. Higgins D.E. Schreiber S. Glimcher L.H. Blumberg R.S. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1075) Google Scholar). In humans, hypomorphic variants of XBP1 are associated with Crohn's disease (Kaser et al., 2008Kaser A. Lee A.H. Franke A. Glickman J.N. Zeissig S. Tilg H. Nieuwenhuis E.E. Higgins D.E. Schreiber S. Glimcher L.H. Blumberg R.S. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1075) Google Scholar). It is likely that mechanisms of similar diversity and complexity operate to resolve inflammation once it has arisen. Below, we illustrate some of the cellular and soluble factors involved. Space is lacking to discuss the many intracellular signaling molecules that impose checks and balances on proinflammatory pathways, such as protein and lipid phosphatases, kinase-inhibiting proteins, ubiquitin ligases, and transcriptional regulators. Perhaps the most important reason that host cell death without microbial involvement rarely triggers nonresolving inflammation is that the death is usually apoptotic; apoptotic cells are ingested by viable cells, typically macrophages; and ingestion of apoptotic cells triggers macrophages to release inflammation-resolving cytokines such as TGF-β and IL-10 (Huynh et al., 2002Huynh M.L. Fadok V.A. Henson P.M. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.J. Clin. Invest. 2002; 109: 41-50Crossref PubMed Scopus (1028) Google Scholar, Kennedy and DeLeo, 2009Kennedy A.D. DeLeo F.R. Neutrophil apoptosis and the resolution of infection.Immunol. Res. 2009; 43: 25-61Crossref PubMed Scopus (276) Google Scholar). Glucocorticoids, whose levels are often increased in response to the stress associated with an inflammatory condition, promote ingestion of apoptotic cells by macrophages and their release of TGF-β and IL-10 (Kennedy and DeLeo, 2009Kennedy A.D. DeLeo F.R. Neutrophil apoptosis and the resolution of infection.Immunol. Res. 2009; 43: 25-61Crossref PubMed Scopus (276) Google Scholar). In contrast, if apoptotic cells are not ingested rapidly, they often progress to necrosis. Necrosis releases products that are agonists, or generate agonists, for host receptors that also detect microbial products and that generate proinflammatory signals. Inflammation can thus be prolonged by a failure of neutrophils to undergo timely apoptosis or by a failure of macrophages to clear those that apoptose. Neutrophil survival is prolonged in many inflammatory states by the ability of GM-CSF and G-CSF to induce the apoptosis inhibitor survivin (Altznauer et al., 2004Altznauer F. Martinelli S. Yousefi S. Thürig C. Schmid I. Conway E.M. Schöni M.H. Vogt P. Mueller C. Fey M.F. et al.Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.J. Exp. Med. 2004; 199: 1343-1354Crossref PubMed Scopus (161) Google Scholar) and the ability of hypoxia inducible factor-1α to induce glycolytic enzymes (Cramer et al., 2003Cramer T. Yamanishi Y. Clausen B.E. Förster I. Pawlinski R. Mackman N. Haase V.H. Jaenisch R. Corr M. Nizet V. et al.HIF-1alpha is essential for myeloid cell-mediated inflammation.Cell. 2003; 112: 645-657Abstract Full Text Full Text PDF PubMed Scopus (1593) Google Scholar) that support ATP generation under hypoxic conditions. Although complement activation is generally proinflammatory, dependence of apoptotic cell clearance on complement implies that inflammation might be prolonged in the face of a deficiency in the complement system (Mevorach et al., 1998Mevorach D. Mascarenhas J.O. Gershov D. Elkon K.B. Complement-dependent clearance of apoptotic cells by human macrophages.J. Exp. Med. 1998; 188: 2313-2320Crossref PubMed Scopus (569) Google Scholar). Likewise, inflammation might be prolonged by deficiency of other factors that promote ingestion of apoptotic cells, such as the secreted glycoprotein milk fat globule-EGF-factor 8 (MFG-E8) (Hanayama et al., 2002Hanayama R. Tanaka M. Miwa K. Shinohara A. Iwamatsu A. Nagata S. Identification of a factor that links apoptotic cells to phagocytes.Nature. 2002; 417: 182-187Crossref PubMed Scopus (1037) Google Scholar), or TIM4, a macrophage receptor for the phosphatidylserine exteriorized by apoptotic cells (Miyanishi et al., 2007Miyanishi M. Tada K. Koike M. Uchiyama Y. Kitamura T. Nagata S. Identification of Tim4 as a phosphatidylserine receptor.Nature. 2007; 450: 435-439Crossref PubMed Scopus (834) Google Scholar). Along with the contrasting impact of encountering apoptotic or necrotic cells, there are other ways in which macrophages normally switch from being proinflammatory at the outset of an inflammatory response to anti-inflammatory later in the process. For example, in wound healing, inflammatory monocytes accumulate in damaged tissue and are essential for its repair (Arnold et al., 2007Arnold L. Henry A. Poron F. Baba-Amer Y. van Rooijen N. Plonquet A. Gherardi R.K. Chazaud B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.J. Exp. Med. 2007; 204: 1057-1069Crossref PubMed Scopus (1397) Google Scholar). In unexplained contrast to the impact of products of necrotic cells, phagocytosis of tissue debris can induce mononuclear phagocytes to switch from a proinflammatory to an anti-inflammatory phenotype that promotes muscle cell differentiation in conjunction with production of elevated amounts of TGF-β (Arnold et al., 2007Arnold L. Henry A. Poron F. Baba-Amer Y. van Rooijen N. Plonquet A. Gherardi R.K. Chazaud B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis.J. Exp. Med. 2007; 204: 1057-1069Crossref PubMed Scopus (1397) Google Scholar). TGF-β is a potent suppressor of what is now called classical macrophage activation (Tsunawaki et al., 1988Tsunawaki S. Sporn M. Ding A. Nathan C. Deactivation of macrophages by transforming growth factor-beta.Nature. 1988; 334: 260-262Crossref PubMed Scopus (754) Google Scholar) and a critical mediator of tissue repair. Tissue damage also promotes production of glucocorticoid hormones. These, too, can convert monocytes/macrophages from a proinflammatory to anti-inflammatory state (Ehr" @default.
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• W4242171500 title "Nonresolving Inflammation" @default.
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• W4242171500 doi "https://doi.org/10.1016/j.cell.2010.02.029" @default.
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