Yali Xu, Ting Su, Hricha Mishra, Naoshi Dohmae, Takehiro Suzuki, Yuriko Sakamaki, Haruyo Aoyagi, Hideki Aizaki, Hajime Nishimura, Erina Furuhata, Yuqing Gong, Qi Cheng, Beiyuan Zhang, Chenzhe He, Kaori Yanaka, Yutaka Furutani, Hideki Tatsukawa, Harukazu Suzuki, Wenkui Yu, Xian-Yang Qin
Sepsis-associated liver dysfunction is a life-threatening condition with a high mortality rate and no mechanism-based therapy. In this study, we identify the cross-linking enzyme transglutaminase 2 (TG2) as a driver of liver inflammation by activating macrophages in a mouse model of sepsis. Pharmacological inhibition of TG2 improves survival and reduces multiorgan inflammation, with the liver as a primary therapeutic target. Mechanistically, TG2 activity was up-regulated in macrophages, where it cross-linked vimentin to promote oligomerization and intermediate filament remodeling. Genetic ablation of TG2 or vimentin suppressed macrophage cytokine production and attenuated lipopolysaccharide-induced inflammation. Notably, vimentin-deficient macrophages exhibited enhanced proteasome recruitment to detergent-insoluble protein aggregates, accelerating the degradation of proinflammatory mediators such as Traf6, thereby dampening nuclear factor κB signaling. Proteomic profiling revealed a previously unrecognized Rab27a-positive vesicle trafficking pathway for inflammatory aggregate clearance. Together, these findings define a TG2-vimentin axis that controls macrophage activation through proteostasis regulation, linking cytoskeletal remodeling to inflammatory signaling.