Loss of intestinal sympathetic innervation elicits an innate immune driven colitis

Molecular Medicine

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[1] 0000 0001 2337 2892, grid.10737.32, Institute of Molecular and Cellular Pharmacology, Nice Sophia Antipolis University, 660 Route des Lucioles, 06560, Valbonne, France;0000000084992262, grid.7177.6, Amsterdam UMC, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;0000000084992262, grid.7177.6, Amsterdam UMC, Department of Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;0000000084992262, grid.7177.6, Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands;Galvani Bioelectronics, Gunnels Wood Road, SG1, 2NY, Stevenage, Hertfordshire, UK;grid.452317.6, Charles River Laboratories, Discovery, De Mudden 16, 9747 AW, Groningen, The Netherlands;

关键词: Inflammatory bowel disease;    Colitis;    Autonomic nervous system;    Sympathetic innervation;    Norepinephrine;   

DOI  :  10.1186/s10020-018-0068-8

来源: publisher

【 摘 要 】

BackgroundBoth the parasympathetic and sympathetic nervous system exert control over innate immune responses. In inflammatory bowel disease, sympathetic innervation in intestinal mucosa is reduced. Our aim was to investigate the role of sympathetic innervation to the intestine on regulation of the innate immune responses.MethodsIn lipopolysaccharide (LPS)-stimulated macrophages, we evaluated the effect of adrenergic receptor activation on cytokine production and metabolic profile. In vivo, the effect of sympathetic denervation on mucosal innate immune responses using 6-hydroxydopamine (6-OHDA), or using surgical transection of the superior mesenteric nerve (sympathectomy) was tested in Rag1−/− mice that lack T- and B-lymphocytes.ResultsIn murine macrophages, adrenergic β2 receptor activation elicited a dose-dependent reduction of LPS-induced cytokines, reduced LPS-induced glycolysis and increased maximum respiration. Sympathectomy led to a significantly decreased norepinephrine concentration in intestinal tissue. Within 14 days after sympathectomy, mice developed clinical signs of colitis, colon oedema and excess colonic cytokine production. Both 6-OHDA and sympathectomy led to prominent goblet cell depletion and histological damage of colonic mucosa.ConclusionsWe conclude that the sympathetic nervous system plays a regulatory role in constraining innate immune cell reactivity towards microbial challenges, likely via the adrenergic β2 receptor.

【 授权许可】

CC BY