MDP-induced interleukin-1β processing requires Nod2 and CIAS1/NALP3

Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (AIDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome I (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1 beta, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that AIDP-induced IL-1 beta release requires Nod2 and CIASI/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, AIDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-I beta production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.