Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation.

Summary

This mechanistic study identifies TG2 as a driver of sepsis-associated liver inflammation and multiorgan injury. TG2 cross-links vimentin in macrophages, altering proteostasis and sustaining NF-κB-related inflammatory signaling; genetic deletion or pharmacological inhibition of TG2 improved outcomes in septic mice.

Key Findings

• TG2 activity was increased in macrophages and promoted liver inflammation in septic mice.
• TG2 cross-linked vimentin, promoting oligomerization, intermediate filament remodeling, and inflammatory macrophage activation.
• Genetic or pharmacological inhibition of TG2 improved survival and reduced multiorgan inflammation.
• Vimentin deficiency enhanced proteasome recruitment and degradation of proinflammatory mediators such as Traf6.

Clinical Implications

TG2 inhibition could become a candidate treatment for sepsis-associated liver dysfunction and systemic inflammation, but clinical translation requires validation of target engagement, safety, and therapeutic timing in human sepsis.

Limitations

• The principal efficacy evidence was generated in mouse and cellular models, whose translation to human sepsis remains uncertain.
• The supplied abstract does not provide the clinical sample size or detailed pharmacokinetic and toxicity information for TG2 inhibition.

Future Directions

Future work should validate the TG2–vimentin axis in human sepsis, define the optimal therapeutic window, develop selective TG2 inhibitors, and test efficacy alongside standard antimicrobial and organ-support therapies.