Cell-intrinsic functions of inflammatory caspases in human diseases

Inflammatory caspases, which include caspase-1, caspase-4 and caspase-5, promote inflammation and antimicrobial immunity by regulating two key processes – the release of proinflammatory cytokines and danger signals and pyroptotic host cell death. Distinct cell-intrinsic substrates of caspases are likely to mediate cytokine release or pyroptosis but the precise mechanisms are unclear.

We want to test which caspase-1 substrates mediate cytokine release and/or pyroptosis. Deregulated cytokine release, seen in hereditary autoinflammatory syndromes, is a result of mutations in proteins, such as NLRP3, which lead to constitutive activation of Caspase-1. Data mining of exome sequences revealed several nonsynonymous single nucleotide polymorphisms (nsSNPs) in Caspase-1 substrates, which alter their susceptibility to proteolytic cleavage. We hypothesise that these missense mutations could also affect inflammation if they enhance cytokine release and/or pyroptosis. We will therefore test the phenotypic consequences of nsSNPs on caspase-1-dependent responses.

These mechanistic and phenotypic data will lay the foundation for a future project to study caspase-1 substrates in donor-derived myeloid cells differentiated from inducible pluripotent stem cells (iPSCs). We will examine the molecular links between cell-autonomous activities of caspases and human inflammatory diseases.