TRAP1 deficiency exacerbates LPS-induced sepsis by modulating macrophage-mediated inflammatory responses

Abstract

Sepsis is a deadly disease resulting from aberrant immune response to microbial infection, which often leads to systemic inflammation and diffuse organ damage. Mitochondrial dysfunction and oxidative stress are central in driving its pathogenesis. TRAP1 (TNF receptor-associated protein 1), a mitochondrial homolog of the Hsp90 (heat shock protein 90), has been implicated in the regulation of mitochondrial protein quality control and cellular stress responses. However, its involvement in inflammatory diseases, including sepsis, remains poorly understood. In this study, lipopolysaccharide (LPS), a critical element of the cell walls of Gram-negative bacteria, was utilized to trigger inflammatory response in both in vitro and in vivo models. Following LPS treatment, TRAP1 knockout (KO) mice exhibited higher mortality and exacerbated lung injury compared to the wild type (WT). Notably, TRAP1 KO mice showed increased macrophage infiltration in lung tissues. Further analysis of peritoneal macrophages, reflecting the systemic inflammatory response, revealed significantly elevated mRNA levels of pro-inflammatory cytokines, including IL-6, IL-1β, TNF-α, and the enzyme, iNOS (inducible nitric oxide synthase). This was associated with enhanced activation of the upstream transcription factor NF-κB. In vitro, TRAP1 knockdown in RAW 264.7 cells similarly led to increased NF-κB activation and mRNA expression of pro-inflammatory cytokines. Additionally, combination treatment with LPS and the TRAP1 inhibitor SB-U015 further increased the accumulation of both intracellular and mitochondrial ROS. Together, TRAP1 may exert a protective effect in sepsis by modulating mitochondrial function and mitigating oxidative stress, particularly in macrophages. Enhancing TRAP1 expression or activity may represent an effective therapeutic approach for sepsis and other inflammatory disorders characterized by macrophage-driven inflammation.