TY - JOUR
T1 - Sympathetic Innervation Modulates Mucosal Immune Homeostasis and Epithelial Host Defense
AU - Mallesh, Shilpashree
AU - ten Hove, Anne S.
AU - Schneider, Reiner
AU - Schneiker, Bianca
AU - Efferz, Patrik
AU - Kalff, J. rg C.
AU - de Jonge, Wouter J.
AU - Wehner, Sven
N1 - Funding Information: This research was funded by the Deutsche Forschungsgemeinschaft (DFG) by a personal grant (WE4204/3-1) to S.W. and by the ImmunoSensation2 Cluster of Excellence, grant number EXC 2151–390873048. Publisher Copyright: © 2022 by the authors.
PY - 2022/8/21
Y1 - 2022/8/21
N2 - Intestinal mucosal cells, such as resident macrophages and epithelial cells, express adrenergic receptors and are receptive to norepinephrine, the primary neurotransmitter of the sympathetic nervous system (SNS). It has been suggested that the SNS affects intestinal immune activity in conditions, such as inflammatory bowel disease; however, the underlying mechanisms remain ambiguous. Here, we investigated the effect of SNS on mucosal immune and epithelial cell functions. We employed 6-OHDA-induced sympathetic denervation (cSTX) to characterize muscularis-free mucosal transcriptomes by RNA-seq and qPCR, and quantified mucosal immune cells by flow cytometry. The role of norepinephrine and cytokines on epithelial functions was studied using small intestinal organoids. cSTX increased the presence of activated CD68+CD86+ macrophages and monocytes in the mucosa. In addition, through transcriptional profiling, the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ were induced, while Arg-1 and CD163 expression was reduced. Further, cSTX increased intestinal permeability in vivo and induced genes involved in barrier integrity and antimicrobial defense. In intestinal organoids, similar alterations were observed after treatment with proinflammatory cytokines, but not norepinephrine. We conclude that a loss in sympathetic input induces a proinflammatory mucosal state, leading to reduced epithelial barrier functioning and enhanced antimicrobial defense. This implies that the SNS might be required to maintain intestinal immune functions during homeostasis.
AB - Intestinal mucosal cells, such as resident macrophages and epithelial cells, express adrenergic receptors and are receptive to norepinephrine, the primary neurotransmitter of the sympathetic nervous system (SNS). It has been suggested that the SNS affects intestinal immune activity in conditions, such as inflammatory bowel disease; however, the underlying mechanisms remain ambiguous. Here, we investigated the effect of SNS on mucosal immune and epithelial cell functions. We employed 6-OHDA-induced sympathetic denervation (cSTX) to characterize muscularis-free mucosal transcriptomes by RNA-seq and qPCR, and quantified mucosal immune cells by flow cytometry. The role of norepinephrine and cytokines on epithelial functions was studied using small intestinal organoids. cSTX increased the presence of activated CD68+CD86+ macrophages and monocytes in the mucosa. In addition, through transcriptional profiling, the proinflammatory cytokines IL-1β, TNF-α, and IFN-γ were induced, while Arg-1 and CD163 expression was reduced. Further, cSTX increased intestinal permeability in vivo and induced genes involved in barrier integrity and antimicrobial defense. In intestinal organoids, similar alterations were observed after treatment with proinflammatory cytokines, but not norepinephrine. We conclude that a loss in sympathetic input induces a proinflammatory mucosal state, leading to reduced epithelial barrier functioning and enhanced antimicrobial defense. This implies that the SNS might be required to maintain intestinal immune functions during homeostasis.
KW - antimicrobial peptides
KW - epithelial cell function
KW - intestinal barrier function
KW - microbial composition
KW - sympathetic denervation
KW - tight junction
UR - http://www.scopus.com/inward/record.url?scp=85136661963&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11162606
DO - https://doi.org/10.3390/cells11162606
M3 - Article
C2 - 36010681
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 16
M1 - 2606
ER -