The Role of Inflammasomes in LPS and Gram-Negative Bacterial Sepsis

Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-α and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies.