NLRP12 suppresses host innate immune signaling to limit inflammation during emergency hematopoiesis (INM6P.404)

Abstract

Abstract The hematopoietic system is capable of rapidly increasing myeloid cell production in response to tissue damage. NLRP12 is expressed in peripheral leukocytes and by osteoclasts and marrow progenitor cells. This NLR family member has been controversial but has been implicated in regulation of innate immune responses. We hypothesized that NLRP12 is a central regulator of innate immune reconstitution following an emergency hematopoietic event. To test this, wild type and Nlrp12-/- C57BL/6 female mice underwent a radiation-thermal combined injury (RCI) consisting of a 20% total body surface area, full thickness contact burn in addition to receiving a single whole body dose of 5 Gy γ-radiation. Following RCI, NLRP12-deficient mice display a lack of peripheral innate immune cell reconstitution as seen in wild type mice; specifically a ten-fold decrease in total numbers of splenic and pulmonary neutrophils and immature monocytes compared to wild type, and a three-fold increase in apoptosis of bone marrow granulocyte/monocyte progenitor cells resulting in a three-fold reduction of total bone marrow cells. Lack of NLRP12 results in a sustained increase in inflammation after injury, with significant increase in serum levels of TNFα, IL-6, IL-12, and type I interferons compared to injured, wild type mice that is inflammasome-independent. These data suggest that NLRP12 acts as an important regulator of inflammation during events that trigger immune hematopoeisis and reconstitution.