Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice via reducing Gasdermin D

Abstract

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.

Neutrophil extracellular traps in central nervous system (CNS) diseases

“…The function of NE is to facilitate the destruction of histone-DNA binding via catalyzing and cleaving histones ( Kumar et al, 2018 ; Wei et al, 2022 ). After decondensation, DNA strands decorated with histones and granule proteins are released extracellularly assisted by gasdermin D, a membrane protein functioning in the formation of pores ( Shang et al, 2022 ; Vats et al, 2022 ). The release of NETs contributes to the further process in physiological and pathological conditions of organisms.…”

Neutrophils in the Focus: Impact on Neuroimmune Dynamics and the Gut–Brain Axis

“…Neutrophils extrude their contents through blebbing from the cell membrane while remaining alive and retaining their functional capabilities [307]. The orchestrated activation of various signaling pathways leads to the blebbing process from and extracellular release of NETs from the neutrophil cell membrane aided by gasdermin D, while neutrophils remain alive and retain their functional capabilities [307,319,320]. Interestingly, different stimuli and disease contexts can trigger distinct forms of production and NET release, including suicidal or lytic NETosis, where neutrophils undergo cell death concurrent with NET expulsion triggered by infections, cytokines, and platelet activation.…”

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation

“…Xuebijing Injection has been shown to significantly inhibit NETosis. 133,134 Some of the active compounds of herbal medicines such as terpenoid triptolide and andrographolide have been shown to be effective in inhibiting NETs, but specific mechanisms are not yet known. Herbal medicine is a treasure for researchers looking to discover active molecules in the treatment of inflammatory diseases related to NETs.…”