Extracellular histones in tissue injury and inflammation.

Neutrophil NETosis is an important element of host defense as it catapults chromatin out of the cell to trap bacteria, which then are killed, e.g., by the chromatin's histone component. Also, during sterile inflammation TNF-alpha and other mediators trigger NETosis, which elicits cytotoxic effects on host cells. The same mechanism should apply to other forms of regulated necrosis including pyroptosis, necroptosis, ferroptosis, and cyclophilin D-mediated regulated necrosis. Beyond these toxic effects, extracellular histones also trigger thrombus formation and innate immunity by activating Toll-like receptors and the NLRP3 inflammasome. Thereby, extracellular histones contribute to the microvascular complications of sepsis, major trauma, small vessel vasculitis as well as acute liver, kidney, brain, and lung injury. Finally, histones prevent the degradation of extracellular DNA, which promotes autoimmunization, anti-nuclear antibody formation, and autoimmunity in susceptible individuals. Here, we review the current evidence on the pathogenic role of extracellular histones in disease and discuss how to target extracellular histones to improve disease outcomes

Physiology and Pathophysiology of Wound Healing in Diabetes

Wound healing is a dynamic process comprising of overlapping phases of hemostasis, inflammation, proliferation, and remodeling that involve multiple cell types. This highly organized and coordinated series of processes result in the restoration of tissue integrity. Deregulation in any of these processes leads to a delayed or nonhealing phenotype as seen in diabetic foot ulcers (DFUs). The functions and cell-to-cell communication between different cell types contributing to wound healing (keratinocytes, fibroblasts, endothelial cells, neutrophils, and macrophages) and their deregulation in chronic nonhealing ulcers are discussed in detail. The balance of signaling factors, including growth factors and gene expression regulators such as microRNA, and their spatiotemporal control is indispensable for successful wound healing, while their dysregulation contributes to pathophysiology of DFUs. Additional factors that contribute to the delayed healing seen in diabetes include macro- and microvascular, neuropathic, immune functions, and microbiome abnormalities. Novel therapeutic approaches including cell therapy, stem cells, and micrografting that provide perspective on how to efficiently treat patients with DFUs are also discussed