NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

Abstract

Histiocytic sarcoma is an uncommon malignancy in both humans and veterinary species. Research exploring the pathogenesis of this disease is scarce; thus, diagnostic and therapeutic options for patients are limited. Recent publications have suggested a role for the NLR, NLRX1, in acting as a tumor suppressor. Based on these prior findings, we hypothesized that NLRX1 would function to inhibit tumorigenesis and thus the development of histiocytic sarcoma. To test this, we utilized Nlrx1−/− mice and a model of urethane-induced tumorigenesis. Nlrx1−/− mice exposed to urethane developed splenic histiocytic sarcoma that was associated with significant up-regulation of the NF-λB signaling pathway. Additionally, development of these tumors was also significantly associated with the increased regulation of genes associated with AKT signaling, cell death and autophagy. Together, these data show that NLRX1 suppresses tumorigenesis and reveals new genetic pathways involved in the pathobiology of histiocytic sarcoma.

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

“…Prior studies evaluating NLRX1 in cancer have found a role for NLRX1 in the regulation of macrophage proliferation (11). Specifically, macrophages harvested from Nlrx1 −/− mice demonstrated a significant increase in proliferation under specific physiological conditions (11).…”

“…Specifically, macrophages harvested from Nlrx1 −/− mice demonstrated a significant increase in proliferation under specific physiological conditions (11). Following TBI, microglia in the lesion area undergo proliferation in response to injury and play vital roles in both the modulation of secondary injury and recovery (26, 27).…”

“…NLRX1 has been previously shown to negatively regulate NF-κB signaling and this attenuation is correlated with increased proliferation and tumorigenesis in cancer models (11, 29). Thus, we next profiled gene expression to evaluate NF-κB signaling following TBI in the Nlrx1 −/− and wild type brain following CCI injury.…”

“…NLRX1 is of particular interest in the context of brain injury as it has been shown to play a role in a variety of different cellular processes important to injury pathogenesis in a diverse range of cell types and tissues. For example, NLRX1 negatively regulates NF-κB signaling, type I interferon (IFN) signaling and reactive oxygen species (ROS) production, as well as, acts as a positive regulator of autophagy in macrophages and fibroblasts (11, 13–15). NLRX1 has been best characterized in the context of pathogen recognition (13, 15, 16).…”

“…NLRX1 has been best characterized in the context of pathogen recognition (13, 15, 16). However, recent studies have extended the function of NLRX1 beyond this initial role in modulating host-pathogen interactions and identified contributions to cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, and the modulation of cell death (11, 17–19). …”