TY - JOUR
T1 - Sympathetic denervation alters the inflammatory response of resident muscularis macrophages upon surgical trauma and ameliorates postoperative ileus in mice
AU - Mallesh, Shilpashree
AU - Schneider, Reiner
AU - Schneiker, Bianca
AU - Lysson, Mariola
AU - Efferz, Patrik
AU - Lin, Eugene
AU - de Jonge, Wouter J.
AU - Wehner, Sven
N1 - Funding Information: Funding: This research was funded by ImmunoSensation2 Cluster of Excellence, grant number EXC 2151–390873048, and a Deutsche Forschungsgemeinschaft (DFG) of Prof. Dr. rer. Nat. Sven Wehner, grant number WE4204/3-1. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motil-ity disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denerva-tion with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an im-portant mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-in-flammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflam-matory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.
AB - Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motil-ity disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denerva-tion with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an im-portant mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-in-flammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflam-matory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.
KW - CX3CR1 macrophages
KW - Muscularis externa
KW - Neuroimmune interactions
KW - Postoperative ileus
KW - Sympathetic denervation
UR - http://www.scopus.com/inward/record.url?scp=85108595561&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms22136872
DO - https://doi.org/10.3390/ijms22136872
M3 - Article
C2 - 34206766
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 13
M1 - 6872
ER -