Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis

Abstract

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

Analysis of signature genes and association with immune cells infiltration in pediatric septic shock

“…The expression of S100A9 was significantly elevated in the in vitro model of endotoxin tolerance, suggesting that S100A9 may be a novel biomarker of endotoxin tolerance and providing valuable information for immunotherapy in patients with sepsis shock ( 38 ). Furthermore, blockade of S100A9 can reduce the infiltration and activation of neutrophil and prevent sepsis-related pulmonary edema and tissue damage, suggesting that S100A9 may be a key target for alleviating sepsis-related injury ( 39 ).…”

Ginkgolic acid promotes inflammation and macrophage apoptosis via SUMOylation and NF-κB pathways in sepsis

“…The levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the blood of septic mice were significantly increased after treatment with GA. In addition, in the CLP model, septic mice are first infected in the abdominal cavity, where abdominal bacteria invade the organs and blood, causing local and systemic inflammatory responses ( 41 ). Therefore, we observed the expression of inflammatory factors in the PMs of septic mice.…”

Identification of novel biomarkers in septic cardiomyopathy via integrated bioinformatics analysis and experimental validation

“…S100A9 is a calcium- and zinc-binding protein that plays an important role in regulating inflammatory processes and immune responses. S100A9 is a pro-inflammatory alarmin that is upregulated in inflamed tissues ( Ding et al, 2021 ). Numerous studies have shown that S100A9 is upregulated in various inflammatory and infectious diseases, including sepsis and patients with severe COVID-19 infection ( Chen et al, 2020a ; Dubois et al, 2019 ; Holzinger et al, 2019 ; Liao et al, 2021 ; Marinkovic et al, 2020 ; Wang et al, 2014 ).…”