missing link gets 11 points

Innate immune system detects the presence of structural components of microbes/viruses/fungi and alerts the adaptive immune system. Toll-like receptors are so far the most studied class of these innate sensors (recognized with Nobel Prize in Physiology or Medicine 2011). However, there is another class of innate sensors represented by cytosolic NOD-like receptors (NLRs)/caspase-1 pathway. This class of sensors form so called inflammasome complexes that detect virulence factors derived from microbes/viruses/fungi. Activation of caspase-1 cleaves pro-IL-1beta into active IL-1beta, releases active IL-1alpha and causes cell death called pyroptosis. Earlier studies have shown that caspase-1 deficient mice are resistant to endotoxin-induced septic shock, a mouse model of sepsis.

If you are interested to know more about inflammasome, I will recommend to read the following article published in Nature. I personally think that this article is the best immunology paper published so far this year. This study by Nobuhiko Kayagaki et al. (1), examined the activation of inflammasome by cholera toxin component B (CTB). While LPS-primed macrophages from B6 and other commonly used mice strains responded to CTB by producing active IL-1beta, LPS-primed macrophages from 129S6 strain failed to respond to CTB. It turned out that 129S6 mouse has a mutation in caspase-11 gene. By creating caspase-11 deficient B6 mice the authors confirmed that the failure of 129S6 mice to respond to CTB was indeed related to caspase-11 mutation. In addition to CTB, both caspase-11 deficient B6 mouse and 129S6 failed to release IL-1beta (via caspase-1 pathway) in response to E. coli, C. rodentium and V. cholerae, but responded to ATP, LLO, MSU, nigericin and others. Failure to activate this caspase-11-dependent, but caspase-1-independent non-canonical inflammasome pathway resulted in reduced IL-1alpha release and reduced cell death (pyroptosis). By analyzing available caspase-1 deficient mice, the authors showed that they were deficient in caspase-11 as well, because they were derived from 129 mouse ES cells. These results raised the question about interpretation of the data derived from caspase-1 deficient mice experiments. By creating caspase-1 KO/caspase-11 transgenic mouse, the authors showed finally that endotoxin-induced septic shock was mediated by caspase 11, not caspase 1, as originally thought. How caspase-11 mediates LPS toxicity is not clear. It could be related to pyroptosis.

This serendipitous discovery will lead to the better understanding of sepsis immuno-pathology and ultimately will lead to improvement in treatment outcome.

David Usharauli