Sepsis and ARDS: The Dark Side of Histones

Figure 1

Proposed mechanisms of extracellular histones in the development of sepsis and ALI/ARDS. In response to various physical challenges (e.g., trauma, infection), polymorphonuclear neutrophils (PMN) and macrophages are recruited and activated through complement interaction (C5a and C5a receptors), which is often needed for extracellular histones presented in ALI/ARDS models. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released. Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. They can also act on TLR2, TLR4, and TLR9 and activate the NLRP3 inflammasome to amplify inflammatory responses by the growing release of cytokines and other mediators. Moreover, circulating histones may also enhance coagulation disorders by acting on TLR2 and TLR4. On the other hand, extracellular histones perpetuate detrimental cell/tissue injury and could in turn induce the formation of NETs by activating the NLRP3 inflammasome, which together lead to more histones being released and greater severity of sepsis and ALI/ARDS.