Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/ijms22136872
Keywords
sympathetic denervation; CX3CR1(+) macrophages; muscularis externa; neuroimmune interactions; postoperative ileus
Funding
- ImmunoSensation2 Cluster of Excellence [EXC 2151-390873048]
- Deutsche Forschungsgemeinschaft [WE4204/3-1]
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The sympathetic nervous system plays a crucial role in noninfectious postoperative inflammation by modulating the anti-inflammatory genes of macrophages and the gene profile of the muscularis externa, ultimately leading to faster recovery of bowel motility in the late phase of postoperative ileus. Denervation results in a shift towards a proinflammatory status and reduced leukocyte infiltration into the muscularis, thus promoting quicker recovery during postoperative ileus.
Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of beta 2-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 motility 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 denervation 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 important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory 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.
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