Effect of TRIM67 knockout on inflammation and macrophage survival in Salmonella Typhimurium-infected mice

Abstract

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a pathogenic bacterium that causes acute gastroenteritis. Macrophages play a crucial role in modulating inflammatory responses and eliminating S. Typhimurium infections. In this study, we identified TRIM67, a tripartite motif protein, as a key mediator of macrophage immunity against S. Typhimurium infection. Using S. Typhimurium mouse models, we evaluated the impact of TRIM67 deficiency on liver and spleen inflammation under both normal physiological conditions and S. Typhimurium infection. Mechanistic insights into TRIM67-mediated inflammatory effects were investigated through immunohistochemistry and Western blotting. For in vitro experiments, primary peritoneal macrophages were isolated from Wild-Type(WT) and TRIM67-knockout(KO) mice, and generated TRIM67-overexpressing RAW 264.7 macrophage cell lines. We assessed bacterial load, survival rates, and macrophage-mediated immune responses following S. Typhimurium infection. Our results demonstrated that KO mice exhibited heightened susceptibility to S. Typhimurium infection compared to WT mice. TRIM67 knockout suppressed inflammation in the liver and spleen, impaired monocyte recruitment to infection sites, and reduced macrophage numbers, ultimately leading to increased mortality. Furthermore, TRIM67 knockout inhibited the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, thereby attenuating macrophage immunity and the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. This study unveils a novel role for TRIM67 in protecting mice against S. Typhimurium infection by regulating inflammation and macrophage survival.