NLRX1 Regulates Effector and Metabolic Functions of CD4+ T Cells

Abstract

Nucleotide oligomerization domain (NOD) like receptor X1 (NLRX1) has been implicated in viral response, cancer progression and inflammatory disorders; however, its role as a dual modulator of CD4+ T cell function and metabolism has not yet been defined. The loss of NLRX1 results in increased disease severity, populations of T helper 1 and T helper 17, and inflammatory markers (IFNγ, TNFα, and IL-17) in mice with DSS colitis. To further characterize this phenotype, we employed in vitro CD4+ T cell differentiation assays and show that NLRX1 deficient T cells have a greater ability to differentiate into inflammatory phenotype and greater proliferation rates. Further, NLRX1−/− cells have a decreased responsiveness to immune checkpoint pathways and greater rates of lactate dehydrogenase activity. When metabolic effects of the knockout are impaired, NLRX1 deficient cells do not display significant differences in differentiation or proliferation. To confirm the role of NLRX1 specifically in T cells, we used an adoptive transfer model of colitis. Rag2−/− recipient mice of NLRX1−/− naïve or effector T cells experienced increased disease activity and effector T cell populations, while no differences were observed between groups receiving wild-type or NLRX1−/− regulatory T cells. Metabolic effects of NLRX1 deficiency are observed in a CD4-specific knockout of NLRX1 within a C. rodentium model of colitis. The aerobic glycolytic preference in NLRX1−/− effector T cells is combined with a decreased sensitivity to immunosuppressive checkpoint pathways to provide greater proliferative capabilities and an inflammatory phenotype bias leading to increased disease severity.

NLR-Dependent Regulation of Inflammation in Multiple Sclerosis

“…Interestingly, recent studies suggest that in addition to playing prominent roles in the regulation of innate immune cells, NLRX1 can also affect adaptive immunity by inhibiting T cell proliferation and differentiation ( 160 ). In dextran sodium sulfate-induced colitis mouse model, lack of NLRX1 results in enhanced T H 1- and T H 17-related inflammatory cytokines, such as IFN-γ, TNF-α, and IL-17, and consequently increased the severity of the disease ( 160 ). In vitro experiments revealed that Nlrx1 −/− T cells have a greater ability to proliferate and differentiate into T H 17 cells.…”

Identification of regulatory genes through global gene expression analysis of aHelicobacter pylorico-culture system

“…As expected, NLR pathway includes an important number of inflammation-driven genes involved in the formation of inflammasomes, such as NLRP1, NLRP3 and NLRC4 (He, Hara, & Nunez, 2016; Masters et al, 2012) or associated with the activation of other inflammatory mechanisms, mainly the NF-κB or MAPK pathways, such as NOD1 and NOD2 (Zhong et al, 2013). Additionally, several genes of the NLR family hold immunoregulatory functions linked to suppression of inflammation, including NLRP10 and NLRX1 (Imamura et al, 2010; Leber et al, 2018; Leber et al, 2017; Xia et al, 2011). Therefore, NLRs constitute a highly heterogeneous and diverse family of pattern recognition receptors (PPR).…”

“…Ppp1r3e gene encodes a glycogen-targeting subunit of the protein serine/threonine phosphatase of type 1 (PP1), a phosphatase protein involved in the regulation of several cell functions, including gene expression, metabolism and cell death (Ceulemans, Stalmans, & Bollen, 2002; Munro, Ceulemans, Bollen, Diplexcito, & Cohen, 2005). Metabolism is an essential component of the immune response (Leber et al, 2017). Activated cells, including macrophages and dendritic cells, undergo metabolic reprogramming, in which glucose metabolism is increased while oxygen consumption is suppressed, to produce energy at fast speed and initiate the mechanisms required for their activation (Kelly & O’Neill, 2015; Rodriguez-Prados et al, 2010).…”

Modulation of Immune Signaling and Metabolism Highlights Host and Fungal Transcriptional Responses in Mouse Models of Invasive Pulmonary Aspergillosis

“…The steady expression of Nlrx1 in the steroid model and chemotherapeutic model suggests Nlrx1 is relevant to both models of IPA and provides an avenue to link immune responses with metabolism. Recently, it has been shown loss of Nlrx1 results in increased proliferation and differentiation of CD4+ T cells into a pro-inflammatory state 91 . This occurs through decreased responsiveness to immune check point pathways such as those mediated by PD-1 and CTLA-4, enhanced lactate dehydrogenase signaling, and increased expression of HIF-1α in normoxic and hypoxic environments.…”