Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4 + T Cells

J Immunol. 2019 Dec 15;203(12):3407-3415. doi: 10.4049/jimmunol.1900364. Epub 2019 Nov 6.

Abstract

Inflammatory bowel disease (IBD) is a complex autoimmune disease with dysfunction in pattern-recognition responses, including within the NLR family. Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is a unique NLR with regulatory and anti-inflammatory functions resulting in protection from IBD in mouse models. NX-13 is an orally active, gut-restricted novel drug candidate that selectively targets and activates the NLRX1 pathway locally in the gut. In vitro and in vivo efficacy of NLRX1 activation by NX-13 was examined. Oral treatment with NX-13 alleviates disease severity, colonic leukocytic infiltration, and cytokine markers of inflammation in three mouse models of IBD (dextran sulfate sodium, Mdr1a-/-, and CD45RBhi adoptive transfer). Treatment of naive CD4+ T cells with NX-13 in vitro decreases differentiation into Th1 and Th17 subsets with increased oxidative phosphorylation and decreased NF-κB activation and reactive oxygen species. With stimulation by PMA/ionomycin, TNF-α, or H2O2, PBMCs from ulcerative colitis patients treated with NX-13 had decreased NF-κB activity, TNF-α+ and IFN-γ+ CD4+ T cells and overall production of IL-6, MCP1, and IL-8. NX-13 activates NLRX1 to mediate a resistance to both inflammatory signaling and oxidative stress in mouse models and human primary cells from ulcerative colitis patients with effects on NF-κB activity and oxidative phosphorylation. NX-13 is a promising oral, gut-restricted NLRX1 agonist for treating IBD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Benzene Derivatives / administration & dosage
  • Benzene Derivatives / pharmacology
  • Benzene Derivatives / therapeutic use*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / agonists
  • Mitochondrial Proteins / metabolism*
  • Oxidative Phosphorylation / drug effects
  • Oxidative Stress / drug effects
  • Pyridines / administration & dosage
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*

Substances

  • Benzene Derivatives
  • Cytokines
  • Mitochondrial Proteins
  • NLRX1 protein, human
  • NLRX1 protein, mouse
  • NX-13
  • Pyridines
  • Reactive Oxygen Species