The TLR4TRIF-Mediated Activation of NLRP3 Inflammasome Underlies Endotoxin-Induced Liver Injury in Mice

الملخص EN

Administration of heat-killed Propionibacterium acnes renders mice highly susceptible to LPS.

After LPS challenge P.

acnes-primed mice promptly show hypothermia, hypercoagulation (disseminated intravascular coagulation), elevation of serum proinflammatory cytokine levels, and high mortality.

The surviving mice develop liver injury.

As previously reported, IL-18 plays a pivotal role in the development of this liver injury.

Many cell types including macrophages constitutively store IL-18 as biologically inactive precursor (pro) form.

Upon appropriate stimulation exemplified by TLR4 engagement, the cells secrete biologically active IL-18 by cleaving pro-IL-18 with caspase-1.

Caspase-1 is also constitutively produced as a zymogen in macrophages.

Recently, NLRP3, a cytoplasmic pathogen sensor, has been demonstrated to be involved in the activation of caspase-1.

Here, we review the molecular mechanisms for the liver injuries, particularly focusing on the TLR4/NLRP3-mediated caspase-1 activation process, with a brief introduction of the mechanism underlying P.

acnes-induced sensitization to LPS.