NLRP12-deficiency results in TNFα-mediated bone marrow apoptosis during emergency hematopoiesis (INM2P.355)

Abstract The hematopoietic system can rapidly expand in response to tissue damage. NLRP12, expressed in leukocytes and bone marrow cells, has been implicated in regulation of immune responses but remains controversial if it acts as an inflammasome or a regulator of NF-κB signaling. We tested the hypothesis that NLRP12 regulates immune responses and reconstitution as a direct regulator of NF-κB signaling using an emergency hematopoiesis model. To test this, C57BL/6 wild type and Nlrp12-/- female mice underwent a radiation-thermal combined injury (RCI) consisting of 20% total body surface area burn and 5Gy γ-radiation. In wild type mice, we observed elevated NLRP12 expression in target tissues after RCI compared to controls. Following RCI, Nlrp12-/- mice failed to reconstitute peripheral innate neutrophil and monocyte populations, had increased levels of serum TNFα, and TNFα-mediated apoptosis of bone marrow progenitor cells. These data suggest that NLRP12 is essential for immune reconstitution after combined radiation and burn injuries. We have uncovered a central role for NLRP12 in regulating granulopoiesis following immune ablation and NFκB cytokine- and receptor-expression. Accordingly, we propose that NLRP12 acts as an important regulator of NF-κB signaling during events that trigger hematopoeisis, suggesting a novel role of NLRP12 in immune reconstitution following injury and immune depletion.