NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target. [Display omitted] • NLRC5 functions as an innate immune sensor in hemolytic and inflammatory conditions • NLRC5 regulates PANoptosome formation and innate immune cell death, PANoptosis • TLRs and NAD+ regulate NLRC5 expression and ROS production to induce PANoptosis • Deletion of NLRC5 protects mice from colitis, HLH, and hemolytic disease NLRC5 is an innate immune sensor that drives inflammatory cell death in response to NAD+ depletion. NLRC5 interacts with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms in mammalian cells, similar to those in plants. NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target. [ABSTRACT FROM AUTHOR]