Switch Off "Parallel Circuit": Insight of New Strategy of Simultaneously Suppressing Canonical and Noncanonical Inflammation Activation in Endotoxemic Mice.

Sepsis is a life-threatening inflammatory disease with a high mortality rate and huge implicative costs. Lipopolysaccharide (LPS) from gram-negative bacteria activates toll-like receptor 4 (TLR4) and may trigger septic shock. However, potent TLR4 inhibitors TAK-242 and Eritoran have been terminated in phase III clinical trials because of inadequate efficacy. Inspired by the recently discovered intracellular, noncanonical LPS receptors, it is considered that TLR4-mediated canonical and caspase-mediated noncanonical inflammation can be seen as a "parallel circuit" to induce sepsis and endotoxemia. Logically, it is proposed that the dual inhibition of caspase-4/5/11 and TLR4 can be a potential novel strategy to develop new therapeutics for sepsis. To verify the strategy, two potential compounds are found: Luteolin and Diacerein with substantial antiinflammatory activity in vitro and in vivo. The results show that the survival rate of endotoxemic mice treated by these compounds is increased remarkably. LPS-induced organ damage is also prevented. Moreover, these compounds result in physical and mental recovery for endotoxemic mice. Notably, Luteolin exhibits better antiinflammatory activity than TAK-242 at comparable TLR4-inhibitory levels. These findings indicate that simultaneous inhibition of TLR4 and caspase-4/5/11 can be an anticipative strategy defeating sepsis and endotoxemia, which can be translated into significant medical and economic benefits.