Cytosolic sensor NLRP12 drives lytic cell death in response to heme plus PAMPs/TNF
•
NLRP12 forms a PANoptosome with the inflammasome as an integral component
•
Caspase-8/RIPK3 drives PANoptosis downstream of the NLRP12-PANoptosome
•
NLRP12 is upregulated during hemolytic disease and induces pathology
Summary
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-1β 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 PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.
The datasets generated and analyzed during the current study are contained within the manuscript and accompanying extended data figures and tables, and publicly available datasets analyzed can be found in the Gene Expression Omnibus database: GSE133181, GSE34404, GSE136046, GSE102881, GSE168532, GSE58287, GSE40012, GSE171110. Data for patients with CCHFV was obtained from Sequence Read Archive (Accession: PRJNA680886).
•
This paper does not report original code.
•
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon reasonable request.
