NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs

Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1b and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPsmediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.

Automated summary

Cytosolic innate immune sensors, such as NLRP12, play a critical role in host defense and can induce inflammatory cell death. This study found that NLRP12 is activated by heme plus PAMPs or TNF, leading to inflammasome and PANoptosome activation, cell death, and inflammation. By understanding this pathway, it is possible to identify potential drug targets for hemolytic and inflammatory diseases.