Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology

• Type of Material: Article
• Authors: Madelyn Houser, Emory University; William Caudle, Emory University; Jianjun Chang, Emory University; George T Kannarkat, Emory University; Yuan Yang, Emory University; Sean Kelly, Emory University; Danielle Oliver, Emory University; Valerie Joers, Emory University; Kathleen M Shannon, Univ Wisconsin; Ali Keshavarzian, Rush Medical College; Malú Gámez Tansey, Emory University
• Language: English
• Date: 2021-08-19
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40478-021-01240-4
• Title of Journal or Parent Work: ACTA NEUROPATHOLOGICA COMMUNICATIONS
• Volume: 9
• Issue: 1
• Start Page: 139
• End Page: 139
• Grant/Funding Information: This material is also based on work supported by the National Science Foundation under Grant No. DGE-1444932 (MCH)” The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health or the National Science Foundation. The funding agencies had no role in the design of the study, the collection, analysis, and interpretation of data, or in the writing of the manuscript.; Funding was provided by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378 and by NIH grants 5R01NS092122 (MGT) and 1RF1AG057247 (MGT).
• Keywords: Intestine; Life Sciences & Biomedicine; MURINE MODEL; Gut; Neurosciences & Neurology; Inflammation; Colitis; TYROSINE-HYDROXYLASE; PROTEIN; Neurosciences; MOUSE MODEL; DISEASE; VESICULAR MONOAMINE TRANSPORTER; ALPHA-SYNUCLEIN; Immune; INTERFERON-GAMMA; DSS; COLONIC INFLAMMATION; Neurodegeneration; KAPPA-B; Science & Technology; Parkinson's disease; MPTP
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Nursing

Abstract

Background: The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. Methods: We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. Results: High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. Conclusions: This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. Graphical abstract: [Figure not available: see fulltext.]