Cell-type specific control of immune responses mediated by inflammasomes in vivo (INM6P.333)

Abstract

Abstract Upon pathogen recognition, certain cytosolic nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) form multi-protein complexes called inflammasomes, which activate CASPASE-1. CASPASE-1 initiates inflammation by processing IL-1beta and -18 into their active forms, and by inducing a rapid, lytic cell death called pyroptosis. The NLRC4 inflammasome responds to the cytosolic presence of specific bacterial proteins, such as flagellin, via NAIPs. A fundamental question is whether and how activation of innate immune responses triggers pathogen-specific adaptive immune responses. We seek to test the hypothesis that cell-type-specific activation of the inflammasome is sufficient to induce inflammation and adaptive immune responses in vivo. To test our hypothesis, we are using a novel ‘knock-in’ mouse strain. This mouse expresses a fusion protein, which selectively activates the NLRC4 inflammasome. Preliminary data indicate extensive NLRC4-dependent inflammatory disease in mice expressing the fusion protein in myeloid-derived cells.