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

The NLR family CARD domain-containing protein 4 (NLRC4), also known as IPAF, is a critical cytosolic protein that functions as an inflammasome scaffold in the innate immune system. It is activated upon sensing bacterial proteins such as flagellin and components of the type III secretion system (T3SS), typically through collaboration with NAIP (NLR family apoptosis inhibitory protein) sensor proteins [7, 8]. Following activation, NLRC4 oligomerizes to form an inflammasome complex that activates caspase-1, which subsequently processes pro-interleukin-1beta and pro-interleukin-18 into their active forms and triggers pyroptosis [2, 4]. Pathogenic gain-of-function mutations in the NLRC4 gene lead to severe autoinflammatory syndromes, including neonatal-onset multisystem inflammatory disease (NOMID) and life-threatening macrophage activation syndrome (MAS) characterized by extreme elevations in IL-18 [7, 9]. Current therapeutic approaches primarily target the downstream cytokines, such as IL-18 with tadekinig alfa or IL-1 with anakinra, although direct small-molecule inhibitors of NLRC4 are currently in preclinical development for applications in stroke and neurodegeneration [2, 3]. Monitoring serum IL-18 levels serves as a primary biomarker for identifying patients with NLRC4-driven hyperinflammation [7].

Other names

IPAFCLANCARD12ICE-protease activating factorCaspase recruitment domain-containing protein 12NLR family CARD domain-containing 4

Inhibition of the NLRC4-mediated inflammasome assembly or neutralization of the primary downstream pro-inflammatory cytokines (IL-1beta, IL-18, and IFN-gamma) that are excessively produced upon its activation.