MiR-155 regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis

Abstract

Neutrophil extracellular traps (NETs)‐mediated tissue damage is a hallmark in abdominal sepsis. Under certain conditions, microRNAs (miRs) can regulate protein expression and cellular functions. The aim of this study was to investigate the role of miR‐155 in sepsis‐induced NET formation, lung inflammation, and tissue damage. Abdominal sepsis was induced in wild‐type (WT) C57BL/6 and miR‐155 gene‐deficient mice by cecal ligation and puncture (CLP). The amount of DNA–histone complex formation as well as myeloperoxidase (MPO) and citrullinated histone 3 in neutrophils isolated from bone marrow were examined by ELISA and flow cytometry. NETs were detected by electron microscopy in the septic lung. Levels of PAD4 and citrullinated histone 3 were determined by Western blot in the blood neutrophils. Lung levels of MPO, CXC chemokines, and plasma levels of DNA–histone complexes and CXC chemokines were quantified. In vitro studies revealed that neutrophils from miR‐155 gene‐deficient mice had less NETs forming ability than WT neutrophils. In the miR‐155 gene‐deficient mice, CLP yielded much less NETs in the lung tissue compared with WT control. CLP‐induced PAD4 levels, histone 3 citrullination, edema, MPO activity, and neutrophil recruitment in the lung were markedly reduced in the mice lacking miR‐155. Furthermore, tissue and plasma levels of CXCL1 and CXCL2 were significantly lower in the miR‐155 gene‐deficient mice compared with WT after induction of abdominal sepsis. Taken together, our findings suggest that miR‐155 regulates pulmonary formation of NETs in abdominal sepsis via PAD4 up‐regulation and histone 3 citrullination. Thus, targeting miR‐155 could be a useful target to reduce pulmonary damage in abdominal sepsis.

Neutrophil extracellular trap inhibition improves survival in neonatal mouse infectious peritonitis

“…24 , 39 , 40 Furthermore, preclinical studies have shown a great potential for anti-NET strategies in limiting inflammation-associated collateral damage in sepsis models. 23 , 38 , 41 – 43 Our study confirms these earlier reports, in that we found that NET inhibition or NET degradation significantly improved outcomes in a mouse model of neonatal peritonitis. Targeting NETs reduced the levels of inflammatory cytokines in the peritoneal cavity and reduced circulating platelet–neutrophil aggregates, a sensitive marker for systemic platelet activation.…”

Wenshen Yiqi Keli Mitigates the Proliferation and Migration of Cigarette Smoke Extract-Induced Human Airway Smooth Muscle Cells through miR-155/FoxO3a Axis

“…Moreover, Wu et al reported that overexpression of miR-155 promoted the chronic intermittent hypoxia-induced NLRP3 inflammasome activation in renal tubular cells [ 34 ]. Additionally, Hawez et al revealed that miR-155 regulates the pulmonary formation of neutrophil extracellular traps in abdominal sepsis [ 35 ]. More importantly, miR-155 has been noted to be highly expressed in COPD, while miR-155 deficiency notably suppressed CSE-mediated lung inflammation [ 36 ].…”

microRNAs and thrombo-inflammation: relationship in sight

“…Thus, these authors showed that miR-155/ PAD4 interaction after transfection of human neutrophils with miR-155 mimic or inhibitor correlated with NET formation capacity in vitro [50]. Furthermore, miR-155 deficiency in a murine model of abdominal sepsis decreased the intrinsic capacity of neutrophils to generate NETs and attenuated the levels of NETs in the lungs [51 ▪ ].…”