Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway

Abstract

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.

Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

“…This has also been demonstrated in patients with sepsis since a correlation between high serum CitH3 and poor prognosis of sepsis is elucidated [61][62][63]. Novel research into systemic dysfunction in sepsis also identified a higher circulating CitH3 level in serum [64][65][66]. Tian et al implicated that elevated CitH3 is correlated with sepsisinduced acute respiratory distress syndrome and lung dysfunction in patients.…”

“…Tian et al implicated that elevated CitH3 is correlated with sepsis-induced acute respiratory distress syndrome and lung dysfunction in patients. In mechanism, CitH3 activates caspase-1-dependent inflammasome in bone marrow-derived macrophages and bone marrow-derived dendritic cells and induces acute lung injury (ALI) [ 65 ].…”

Activation of toll‐like receptor 4/nuclear factor‐kappa B signaling by triggering a receptor expressed on myeloid cells 1 promotes alveolar macrophage M1 polarization and exacerbates septic acute lung injury

“…Hematoxylin and eosin were subsequently used to stain the sections, 16 followed by visualization under a light microscope at 200× magnification. The severity of ALI was scored as previously described, 17 with the assessment of neutrophils and alveolar macrophages, septal hemorrhage and congestion, septal mononuclear cells/lymphocytes infiltration, alveolar hemorrhage and edema.…”

Sepsis-Induced Acute Lung Injury Is Alleviated by Small Molecules from Dietary Plants via Pyroptosis Modulation

“…Citrullinated histone H3 (CitH3) is a biomarker for NETs formation, a recent study indicated that it promoted ARDS in sepsis via regulating caspase-1-dependent inflammasome pathway . OLFM4 exacerbated lung epithelial cells dysfunction in ARDS induced by sepsis via mediating signaling transduction of NF-κB, which accelerates the assembly of NLRP3/ASC/caspase-1 .…”