Abstract

The NLRP3 inflammasome is a multimeric protein complex consisting of the sensor molecule NACHT, LRR and PYD domains-containing protein 3 (NLRP3), the adaptor molecule Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. Molecules with conserved molecular motifs trigger the assembly of the inflammasome and lead to maturation of pro-inflammatory cytokines that induce a mature inflammatory response. Emerging data suggest that inflammasome activation in antigen presenting cells (APCs), such as dendritic cells (DCs), trigger their activation and ability to activate T cells. Our study asked whether blockade of the cytoplasmic NLRP3-inflammasome components NLRP3 and ASC interfered with alloantigen recognition and allograft rejection. We found that deletion of ASC significantly inhibited DC and T cell alloresponses, whereas deletion of NLRP3 had no effect. Despite the significant in vitro findings, there was no effect of the deletion of NLRP3 or ASC on allogeneic skin graft rejection across a stringent MHC barrier. The conclusion of this study is that while in vitro alloresponses were significantly inhibited by deletion of ASC, allograft rejection across a complete MHC mismatch was not prevented. The results suggest that the NLRP3-inflammasome coreceptor ASC plays a significant role by inhibiting allogeneic APC-induced T cell activation in vitro, independent of its inflammasome related effects.

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