NLRX1 Limits Inflammatory Neurodegeneration in the Anterior Visual Pathway
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ABSTRACT:
PROVIDER: PRJNA1126727 | ENA |
REPOSITORIES: ENA
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Project description:Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple EAE models, we explored the potential of the innate immune sensor NLRX1 to protect neurons in the anterior visual pathway from inflammatory neurodegeneration. To do this, we assessed retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1-/- and wild-type (WT) EAE mice. Our results indicate that Nlrx1-/- mice exhibit significantly increased RGC loss and axonal injury compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis models. Adoptive transfer experiments, in which wild type T cells were transferred into lymphocyte-deficient Rag-/- mice to minimize the effects of Nlrx1 knockout on peripheral lymphocyte priming, revealed more severe microgliosis and astrogliosis in the optic nerve of Nlrx1-/-Rag-/- mice compared to Rag-/- mice, suggesting a regulatory role of NLRX1 in innate immune compartments. Transcriptome analysis in primary astrocytes demonstrated that NLRX1 negatively regulates TLR-mediated NF-κB activation. The novel pharmacologic NLRX1 activator LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66 after the onset of paralysis resulted in less anterior visual pathway neurodegeneration compared to vehicle. These data suggest that a pharmacologic NLRX1 activators attenuates glial immune activation and has the potential to limit inflammatory neurodegeneration in diseases, such as MS, where chronic CNS-compartmentalized inflammation may drive neurodegenerative pathology. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases where chronic compartmentalized innate immune activation and neuroinflammation play a role.
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Project description:NLRX1 is an immune signaling protein that has shown to be both tumor suppressing or tumor promoting, depending on the type of cancer. We demonstrate that NLRX1 has tumor suppressive abilities in vitro in Pan02 cells. We used this microarray to evaluate genes and pathways NLRX1 regulates in these cells to cause the observed in vitro phenotypes. Abstract from associated publication: Pancreatic cancer is a deadly malignancy with limited treatment options. NLRX1 is a unique, understudied member of the Nod-like Receptor (NLR) family of pattern recognition receptors that regulates a variety of biological processes that are highly relevant to pancreatic cancer. The role of NLRX1 in cancer remains highly enigmatic, with some studies defining its roles as a tumor promoter, while others characterize its contributions to tumor suppression. These seemingly contradicting roles appear to be due, at least in part, to cell type and temporal mechanisms. Here, we define roles for NLRX1 in regulating critical hallmarks of pancreatic cancer using both gain-of-function and loss-of-function studies in murine Pan02 cells. Our data reveals that NLRX1 increases susceptibility to cell death, while also suppressing proliferation, migration, and reactive oxygen species production. We also show that NLRX1 protects against upregulated mitochondrial activity and limits energy production in the Pan02 cells. Transcriptomics analysis revealed that the protective phenotypes associated with NLRX1 are correlated with attenuation of NF-kB, MAPK, AKT, and inflammasome signaling. Together, these data demonstrate that NLRX1 diminishes cancer-associated biological functions in pancreatic cancer cells and establishes a role for this unique NLR in tumor suppression.
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Project description:The immune signaling protein NLRX1 can be either tumor promoting or tumor suppressing in different models of cancer. We demonstrate that in a mammary tumor model of triple-negative breast cancer, NLRX1 impacts tumor volume and lung metastasis. We used this microarray to understand what genes and pathways are impacted by NLRX1 in murine triple-negative mammary tumors to produce the in vivo phenotypes we observed. Abstract from associated publication: Prior studies have defined multiple, but inconsistent, roles for NLRX1 in regulating cancer-associated biological functions. Here, we explore the role of NLRX1 in the highly-metastatic murine 4T1 mammary tumor model. Using Nlrx1-/- mice engrafted with 4T1 tumors, we demonstrate that NLRX1 functions as a tumor suppressor when expressed in healthy host cells. Specifically, NLRX1 attenuates tumor growth and metastasis through suppressing epithelial-mesenchymal transition, tumor-associated eosinophil recruitment, and the lung metastatic niche. Conversely, we demonstrate that NLRX1 functions as a tumor promoter when expressed in 4T1 tumor cells using gain- and loss-of-function studies. Mechanistically, NLRX1 augments 4T1 aggressiveness through regulating epithelial-mesenchymal transition, cell death, proliferation, migration, ROS levels, and mitochondrial respiration. Together, we provide critical insight into NLRX1 function in breast cancer and establish cellular context as the director of the dichotomous role of NLRX1 in mammary tumor metastasis.
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Project description:NLRX1 is a mitochondrial-associated NOD-like receptor that modulates antiviral immunity, cellular stress, autophagy, and reactive oxygen species (ROS) production. The role of NLRX1 in inflammatory bowel disease (IBD) remains largely unknown. This study aimed to characterize NLRX1-mediated mechanisms of protection from IBD. We investigated the ability of NLRX1 to modulate global colonic gene expression, gut pathology, inflammation and immunity by using loss-of-function approaches in dextran sodiu sulfate (DSS) and CD4+CD45RBhigh transfer colitis models. Colons, spleens, and mesenteric lymph nodes (MLN) were excised for characterizing immune cell subsets, histological analyses, cytokine, RNA sequencing analyses, and autophagy expression, NF-κB activity, and ROS production. The loss of NLRX1 increased severity of disease and colonic histopathology in both models of IBD. Colons of NLRX1-/- mice had significantly increased epithelial ulceration and leukocyte infiltration mostly in the form of neutrophils, lymphocytes, and macrophages in the DSS model, while recipients of NLRX1-/- CD4+ T cells had increased leukocytic infiltration, proliferation, fibrosis, and crypt abscessation in both colon and ileum. The loss of NLRX1 increased numbers of effector T helper (Th1), Th17, and regulatory T cells (Treg) cells in the colonic mucosa and spleen, increased colonic NF-κB activity, upregulation of IL-17, IFNγ and TNF-α production, and increased ROS production. Global transcriptomic analyses demonstrates that NLRX1 regulates immunity and lipid metabolism pathways. NLRX1 ameliorates intestinal pathology during IBD by acting as an internal thermostat that modulates the balance of effector versus regulatory CD4+ T cell responses, and suppressing colonic NF-κB activity, inflammatory cytokine expression, lipid metabolism gene expression, ROS production and autophagy.
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