NLRP12 limits TNFα-induced apoptosis of monocyte progenitor cells during emergency hematopoiesis

Abstract

Abstract The NLR family member NLRP12, expressed in peripheral leukocytes and bone marrow progenitor cells, is implicated in controlling the response of the innate immune system by suppressing non-canonical NfκB signaling. Given the hematopoietic system’s ability to respond to insults by rapidly increasing myeloid cell production, and the importance of tightly controlled cytokine regulation during these processes, we hypothesized NLRP12 to be a key regulator of the innate immune system’s reconstitution following a hematopoietic emergency. 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 injury, Nrlp12−/− mice showed a three-fold increase in specific apoptosis of granulocyte-monocyte progenitor cells leading to a reduction in the total number of bone marrow cells and thus systemic leukopenia. We also observed that the lack of NLRP12 led to elevated levels of TNFα systemically following injury. Utilization of a neutralizing antibody against TNFα following injury abrogated the granulocyte-monocyte progenitor cell apoptosis and leukopenia seen in vehicle-treated mice. These data lead us to conclude that NLRP12 acts as a suppressor of TNFα signaling during emergency hematopoiesis; a novel finding, since no member of the NLR family has been previously found to interact with TNFα signaling.