NLRX1 attenuates tumorigenesis through the negative regulation of AKT and NF-κB signaling (TUM7P.924)

Abstract

Abstract Members of the NLR family of pattern recognition receptors are essential mediators of the host immune response. Recently, our lab and others identified a novel sub-group of NLRs that function as negative regulators of inflammation. One of the members of this sub-group, NLRX1, is a potent regulator of interferon, NF-κB and autophagy signaling. Each of these signaling pathways has been linked to diverse types of cancer. Thus, we hypothesized that NLRX1 attenuates tumorigenesis through the negative regulation of overzealous innate immune system signaling. To evaluate this hypothesis, we utilized a urethane based model of tumorigenesis and explored disease progression in Nlrx1-/- mice. Mice lacking NLRX1 exhibited dramatically increased morbidity and mortality and were found to develop a rare neoplasia, diagnosed as histiocytic sarcoma. Of the already rare histiocytic disorders in humans, histiocytic sarcoma is exceedingly uncommon and the rarity of this disease has resulted in a paucity of data pertaining to diagnostic and therapeutic options. Mechanistically, our data indicates that NLRX1 attenuates tumorigenesis through the negative regulation of AKT and NF-κB signaling. These pathways were found to be associated with macrophage hyperproliferation in the absence of NLRX1. Our data extends the function of NLRX1 beyond its currently characterized role in host-pathogen defense and reveals a significant contribution for this NLR in cancer pathobiology.