Pyroptosis by caspase-11 inflammasome-Gasdermin D pathway in autoimmune diseases

Inflammasomes are a group of supramolecular complexes primarily comprise a sensor, adaptor protein and an effector. Among them, canonical inflammasomes are assembled by one specific pattern recognition receptor, the adaptor protein apoptosis-associated speck-like protein containing a CARD and procaspase-1. Murine caspase-11 and its human ortholog caspase-4/5 are identified as cytosolic sensors which directly responds to LPS. Once gaining access to cytosol, LPS further trigger inflammasome activation in noncanonical way. Downstream pore-forming Gasdermin D is a Pyroptosis executioner. Emerging evidence announced in recent years demonstrate the vital role played by caspase-11 non-canonical inflammasome in a range of autoimmune diseases. Pharmacological ablation of caspase-11 and its related effector results in potent therapeutic effects. Though recent advances have highlighted the potential of caspase-11 as a drug target, the understanding of caspase-11 molecular activation and regulation mechanism remains to be limited and thus hampered the discovery and progression of novel inhibitors. Here in this timeline review, we explored how caspase-11 get involved in the pathogenesis of autoimmune diseases, we also collected the reported small-molecular caspase-11 inhibitors. Moreover, the clinical implications and therapeutic potential of caspase-11 inhibitors are discussed. Targeting non-canonical inflammasomes is a promising strategy for autoimmune diseases treatment, while information about the toxicity and physiological disposition of the promising caspase-11 inhibitors need to be supplemented before they can be translated from bench to bedside.

Gasdermins; Inflammasomes; Innate immunity and inflammation; Pyroptosis; caspase-11.