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

Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Catherine Bienert, Jyoti Chauhan and Josep Bassaganya-Riera
J Immunol November 6, 2019, ji1900364; DOI: https://doi.org/10.4049/jimmunol.1900364
Andrew Leber
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
†BioTherapeutics, Inc., Blacksburg, VA 24060
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Raquel Hontecillas
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
†BioTherapeutics, Inc., Blacksburg, VA 24060
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  • ORCID record for Raquel Hontecillas
Victoria Zoccoli-Rodriguez
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
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Catherine Bienert
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
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Jyoti Chauhan
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
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Josep Bassaganya-Riera
*Landos Biopharma, Inc., Blacksburg, VA 24060; and
†BioTherapeutics, Inc., Blacksburg, VA 24060
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Key Points

  • NLRX1 activation induces immunometabolic mechanisms to reduce effector CD4+ T cells.

  • NX-13 is a novel NLRX1-targeting therapeutic for IBD.

  • NX-13 is effective in three mouse models of IBD and primary human cells from UC.

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.

Footnotes

  • This work was supported by National Institutes of Health Public Service Grant 1R43DK121561.

  • The online version of this article contains supplemental material.

  • Received March 29, 2019.
  • Accepted October 8, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4+ T Cells
Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Catherine Bienert, Jyoti Chauhan, Josep Bassaganya-Riera
The Journal of Immunology November 6, 2019, ji1900364; DOI: 10.4049/jimmunol.1900364

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Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4+ T Cells
Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Catherine Bienert, Jyoti Chauhan, Josep Bassaganya-Riera
The Journal of Immunology November 6, 2019, ji1900364; DOI: 10.4049/jimmunol.1900364
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Print ISSN 0022-1767        Online ISSN 1550-6606