Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

Abstract

NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil “explosion” and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process.

Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients

“…As described in the previous section, we selected genes showing differential methylation in between-group comparisons, appearing in enrichment analysis in the cnetplots maps and with relevant roles in immunosuppression. Genes selected from the previous section were investigated in terms of their biological relevance in sepsis, based on the different biological processes they were involved in, and the previous findings we and other authors have reported ( 3 – 5 ). This strategy allowed us to select the 10 most relevant candidates ( ILB1, IL10, IL17, IL18, IFNGR2, S100A8, S100A9, TNFAIP8, TREM1, IRAK3 ) for further validation through pyrosequencing.…”

“…The exacerbated hyper-inflammatory response can also damage non-infected tissues and lead to dysfunction of different organs and systems linked to hypotension, vasculature damage, and coagulation events, aggravating the disease status of septic patients, and producing early deaths at the initial stages of sepsis ( 2 ). The hyperinflammatory process is an acute event occurring usually at initial stages of sepsis just after infection ( 3 – 5 ). A compensatory anti-inflammatory response syndrome (CARS) can sometimes simultaneously occur, which can induce long-term immunosuppression, leading to secondary infections and most sepsis-associated late deaths ( 6 , 7 ).…”

To Gain Insights into the Pathophysiological Mechanisms of the Thrombo-Inflammatory Process in the Atherosclerotic Plaque

“…NETs contribute equally to thrombosis, immune response, and tissue damage, making them critical to the development of this disease. NETosis sets off platelets, leads to the release of toxic histones [ 101 , 171 , 172 , 173 ] and active enzymes, hence modifying thrombus stability [ 174 , 175 ]. The assembly of the inflammasome, along with heightened PAD4 activity, leads to the discharge of cytokines that are both pro-inflammatory and pro-thrombotic.…”

Atherosclerosis Progression and COVID 19: The Role of Tromboinflammation

“…NETosis sets off platelets, leads to the release of toxic histones (171)(172)(173) and active enzymes, hence modifying thrombus stability. (174,175) The assembly of the inflammasome, along with heightened PAD4 activity, leads to the discharge of cytokines that are both pro-inflammatory and pro-thrombotic. This also activates the endothelium, further increasing the recruitment of leukocytes as well as inflammasome assembly in adjacent cells.…”