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

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Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease Through Immunometabolic Mechanisms in CD4+ T Cells Activation of NLRX1 by NX-13 Alleviates Inflammatory Bowel Disease through Immunometabolic Mechanisms in CD4+ T Cells This information is current as of September 25, 2021. Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Catherine Bienert, Jyoti Chauhan and Josep Bassaganya-Riera J Immunol published online 6 November 2019 http://www.jimmunol.org/content/early/2019/11/05/jimmun Downloaded from ol.1900364 Supplementary http://www.jimmunol.org/content/suppl/2019/11/05/jimmunol.190036 http://www.jimmunol.org/ Material 4.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 6, 2019, doi:10.4049/jimmunol.1900364 The Journal of Immunology 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*,† 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 Downloaded from infiltration, and cytokine markers of inflammation in three mouse models of IBD (dextran sulfate sodium, Mdr1a2/2, 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-kB activation and reactive oxygen species. With stimulation by PMA/ionomycin, TNF-a,orH2O2, PBMCs from ulcerative colitis patients treated with NX-13 had decreased NF-kB activity, TNF-a+ and IFN-g+ 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 http://www.jimmunol.org/ ulcerative colitis patients with effects on NF-kB activity and oxidative phosphorylation. NX-13 is a promising oral, gut- restricted NLRX1 agonist for treating IBD. The Journal of Immunology, 2019, 203: 000–000. ver 3 million people in America and 5 million world- an unmet clinical need exists for novel targets capable of re- wide suffer from inflammatory bowel disease (IBD). storing immune tolerance and controlling the wide array of im- O This widespread and debilitating illness results in de- mune responses. creased quality of life and significant healthcare related costs NLRs are a family of cytosolic pattern-recognition receptors that (1). The underlying immune dysfunction in Crohn disease (CD) function in surveillance of metabolic stress, discrimination between by guest on September 25, 2021 (2, 3) and ulcerative colitis (UC) (4, 5) is with involvement of pathogenic bacteria versus beneficial symbionts, and recognition of both innate and adaptive immunity culminating in a perturbed inflammatory signaling (8–12). Genetic polymorphisms in several immune tolerance to the gut microbiome and other environ- NLRs have been described in IBD such as NLRC1 (NOD1) and mental factors. Despite this complexity, current therapeutics are NLRC2 (NOD2) (13–15). Although NOD1 and NOD2, in addi- unrefined steroids, immunosuppressants, and neutralizing Abs to tion to inflammasome-associated NLRs, are well-characterized to single cytokines such as TNF-a. Although current treatments for contribute to human disease, a smaller class of negative regulatory IBD have improved (6, 7), these therapies remain modestly NLRs remain relatively unknown. Indeed, genetic abnormalities successful with adverse side effects, including immunosuppres- in these well-characterized NLR genes are linked to IBD patho- sion, increased risk for infection, malignancies, and death. Thus, genesis (16–19). This smaller family of NLRs comprises NLRX1, NLRP12, and NLRC3 and has shown potent effects in the atten- *Landos Biopharma, Inc., Blacksburg, VA 24060; and †BioTherapeutics, Inc., uation of inflammation in nonclinical models of autoimmune and Blacksburg, VA 24060 infectious disease. NLRX1 regulates inflammation and IFN pro- ORCIDs: 0000-0001-9586-9953 (R.H.); 0000-0002-3837-3000 (J.C.); 0000-0001- duction in response to pathogens (20–23) and antagonizes NF-kB 8967-6012 (J.B.-R.). (20, 23, 24). However, many of these preclinical studies focus Received for publication March 29, 2019. Accepted for publication October 8, 2019. solely on the worsening of disease in loss-of-function designs. The This work was supported by National Institutes of Health Public Service Grant ability to modulate function by pharmacologic activation of the 1R43DK121561. receptor, the prevalence of function-disrupting mutations, and Conception and design of the study: A.L. and J.B.-R. Generation and interpretation of data: A.L., R.H., V.Z.-R., C.B., and J.B.-R. Drafting and revision of manuscript: A.L., native expression patterns in response to inflammation is unknown J.C., and J.B.-R. Approval of final version: A.L., R.H., V.Z.-R., J.C., and J.B.-R. in human disease. Address correspondence and reprint requests to Dr. Josep Bassaganya-Riera, Landos NLRX1 is a mitochondria-associated receptor involved in Biopharma, Inc., 1800 Kraft Drive, Suite 216, Blacksburg, VA 24060. E-mail ad- downregulating inflammation during bacterial and viral exposure, dress: [email protected] acute noninfectious colitis, colorectal cancer, and chronic pul- The online version of this article contains supplemental material. 2 2 monary disease (20, 22, 23). NLRX1 / mice with dextran sul- Abbreviations used in this article: CD, Crohn disease; DSS, dextran sulfate sodium; GI, gastrointestinal; IBD, inflammatory bowel disease; LDH, lactate dehydrogenase; fate sodium (DSS) colitis have significantly worse disease activity PMA/I, PMA (5 ng/ml) and ionomycin (500 ng/ml); qRT-PCR, quantitative RT-PCR; associated with more severe gut mucosal inflammation and fi- ROS, reactive oxygen species; Treg, regulatory T cell; UC, ulcerative colitis; WT, brosis when compared with their wild-type (WT) counterparts wild-type. (25). Colonic NLRX1 expression is significantly suppressed in Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 colons of mice with colitis (26). RNA-seq data from colons of WT www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900364 2 NX-13 ALLEVIATES IBD BY IMMUNOMETABOLISM 2 2 and NLRX1 / mice unveil that loss of NLRX1 during colitis fixed and permeabilized for staining of intracellular Ags (IFN-g, Tbet, IL- causes overzealous inflammatory chemokine and cytokine sig- 10, FOXP3, IL-17, RORgT, and IL-4). Data were acquired on a naling (.10-fold increase) in myeloid and epithelial cell response BD FACSCelesta II and analyzed using BD FACSDiva version 9.0 (BD Biosciences). elements such as Il-6, Tnf, Ifng, Il-21, and Mcp1. Previously, we demonstrated that the deficiency of NLRX1 worsens inflammatory Gene expression + responses in vitro in both CD4 T cells and epithelial cells of mice Colon or cells were homogenized within RLT buffer. RNA was isolated and shifts the metabolic preferences of cells. When the metabolic from homogenate by RNAeasy Mini Kit, according to manufacturer’s differences are prevented, the immune effects resulting from the instructions. From RNA, cDNA was produced by iScript reverse tran- loss of NLRX1 are abrogated (25) both in vitro and in vivo that are scriptase. qRT-PCR was conducted with SYBR Green Master Mix. Start- ing quantity was calculated according to standard curve and normalized to integrated with changes in inflammation-associated bacterial taxa b-actin, as previously described. within the colonic microenvironment (27). In line with these beneficial preclinical responses in IBD, we Histopathology have developed 1, 3, 5-tris (6-methylpyridin-2-yloxy) benzene Colons were fixed within 10% buffered formalin, embedded in paraffin, (NX-13), as an orally active, gut-restricted, NLRX1-activating sectioned, and stained with H&E for examination. Colons were scored (0– therapeutic with limited systemic exposure for the treatment of 4) for leukocytic infiltration, mucosal thickening, and epithelial erosion by IBD. NX-13 was generated by medicinal chemistry-based opti- blinded pathologist. mization of novel scaffolds designed to target the previously PBMC culture categorized binding pocket
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