Resolution of inflammation is a coordinated and active process aimed at restoration of tissue integrity and function. This review integrates the key molecular and cellular mechanisms of resolution. We describe how abrogation of chemokine signalling blocks continued neutrophil tissue infiltration and how apoptotic neutrophils attract monocytes and macrophages to induce their clearance. Uptake of apoptotic neutrophils by macrophages reprograms macrophages towards a resolving phenotype, a key event to restore tissue homeostasis. Finally, we highlight the therapeutic potential that derives from understanding the mechanisms of resolution.

The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis—a major underlying cause of mortality worldwide—to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.

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Key Points• Nonanticoagulant heparin is shown to bind histones and provide cytoprotection in mouse models of sterile inflammation and sepsis.Extracellular histones are considered to be major mediators of death in sepsis. Although sepsis is a condition that may benefit from low-dose heparin administration, medical doctors need to take into consideration the potential bleeding risk in sepsis patients who are already at increased risk of bleeding due to a consumption coagulopathy. Here, we show that mechanisms that are independent of the anticoagulant properties of heparin may contribute to the observed beneficial effects of heparin in the treatment of sepsis patients. We show that nonanticoagulant heparin, purified from clinical grade heparin, binds histones and prevents histone-mediated cytotoxicity in vitro and reduces mortality from sterile inflammation and sepsis in mouse models without increasing the risk of bleeding. Our results demonstrate that administration of nonanticoagulant heparin is a novel and promising approach that may be further developed to treat patients suffering from sepsis. (Blood. 2014;123(7):1098-1101) IntroductionSepsis and septic shock are serious clinical problems with high mortality rates for which no adequate treatment currently exists. 1Neutrophils respond to infection with the formation of neutrophil extracellular traps (NETs), 2,3 intricate networks containing DNA as the major structural component and proteins like histones and neutrophil elastase, which have antimicrobial properties. Extracellular histones, however, also exhibit cytotoxic activity toward host cells, including the endothelium. 4,5 Histone release can thus trigger a feedback cascade, resulting in more cell death and additional release of histones.6 Consequently, extracellular histones are considered interesting therapeutic targets for sepsis treatment. 4 Histones are positively charged, and NET-mediated cytotoxicity can be reduced with polysialic acid, a negatively charged polymer. 5 We hypothesized that heparin, a negatively charged polysaccharide, blocks histone cytotoxicity and reduces mortality from sterile inflammation and sepsis. Low dose unfractionated heparin (UFH) has been tested in a clinical trial as a complementary treatment of sepsis. 7 The study rationale linked infection, inflammation, and coagulation in sepsis and sought to inhibit the coagulation part with low doses of heparin so as not to increase the risk of bleeding in a patient who is already at risk due to sepsis-associated consumption coagulopathy. 7,8 Nevertheless, although this study failed to demonstrate a significant benefit on 28-day mortality rate, we hypothesize that the minor beneficial effects of heparin observed might be attributed to a mechanism independent of the anticoagulant properties of heparin. We reasoned that removing the anticoagulant fraction from UFH would yield an antithrombin affinity-depleted heparin (AADH) that neutralizes histone-mediated cytotoxicity and effectively treats sepsis without increasing risk of bleeding....