Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against<i>Salmonella</i>

TLDR

Cytosolic NOD‑like receptors form inflammasomes that activate caspase‑1 and release IL‑1β/IL‑18, but the specific NLRs responding to microbial pathogens in vivo remain poorly defined. Both NLRP3 and NLRC4 activate caspase‑1 and recruit ASC to a shared cytoplasmic focus for IL‑1β processing during Salmonella typhimurium infection, and mice lacking both receptors are highly susceptible, demonstrating redundant NLR‑mediated defense against intracellular pathogens.

Abstract

Intracellular pathogens and endogenous danger signals in the cytosol engage NOD-like receptors (NLRs), which assemble inflammasome complexes to activate caspase-1 and promote the release of proinflammatory cytokines IL-1β and IL-18. However, the NLRs that respond to microbial pathogens in vivo are poorly defined. We show that the NLRs NLRP3 and NLRC4 both activate caspase-1 in response to Salmonella typhimurium. Responding to distinct bacterial triggers, NLRP3 and NLRC4 recruited ASC and caspase-1 into a single cytoplasmic focus, which served as the site of pro–IL-1β processing. Consistent with an important role for both NLRP3 and NLRC4 in innate immune defense against S. typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo.