NLR family CARD domain-containing protein 4 inflammasome (NLRC4)

The NLRC4 (NLR family CARD domain-containing protein 4) inflammasome is a cytosolic multi-protein complex essential for the innate immune response against intracellular bacterial pathogens (UniProt Q9NPP4). It is activated by the detection of bacterial flagellin or type III secretion system (T3SS) components via NAIP (NLR family apoptosis inhibitory protein) sensors (PMID: 30104658). Once activated, NLRC4 undergoes oligomerization and recruits pro-caspase-1, which then processes pro-inflammatory cytokines IL-1β and IL-18 into their active forms and triggers pyroptosis through gasdermin D cleavage (PMID: 30104658). Gain-of-function mutations in the NLRC4 gene lead to severe autoinflammatory syndromes, including NLRC4-associated macrophage activation syndrome (MAS) and infantile enterocolitis, characterized by life-threatening cytokine storms (PMID: 25217984). While direct inhibitors of NLRC4 are currently in the discovery phase, clinical management primarily involves the use of IL-1 and IL-18 antagonists to mitigate the systemic inflammatory response (ClinicalTrials.gov NCT04642339). Understanding the structural basis of NLRC4 activation remains a key area of research for developing targeted therapies for autoinflammatory and infectious diseases.

Other names

ICE protease-activating factorIPAFCaspase recruitment domain-containing protein 12CARD12CLANCLAN1

Inhibition of downstream IL-1β and IL-18 signaling or experimental direct inhibition of NLRC4 assembly