Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A

Andreas Körner,Martin Schlegel,Verena Gudernatsch,Torsten Kaussen,Georg Hansmann,Timo Schumacher,Valbona Mirakaj,Martin Giera

doi:10.1038/s41467-019-08328-5

Abstract

The bidirectional communication between the immune and nervous system is important in regulating immune responses. Here we show that the adrenergic nerves of sympathetic nervous system orchestrate inflammation resolution and regenerative programs by modulating repulsive guidance molecule A (RGM-A). In murine peritonitis, adrenergic nerves and RGM-A show bidirectional activation by stimulating the mutual expression and exhibit a higher potency for the cessation of neutrophil infiltration; this reduction is accompanied by increased pro-resolving monocyte or macrophage recruitment, polymorphonucleocyte clearance and specialized pro-resolving lipid mediators production at sites of injury. Chemical sympathectomy results in hyperinflammation and ineffective resolution in mice, while RGM-A treatments reverse these phenotypes. Signalling network analyses imply that RGM-A and β2AR agonist regulate monocyte activation by suppressing NF-κB activity but activating RICTOR and PI3K/AKT signalling. Our results thus illustrate the function of sympathetic nervous system and RGM-A in regulating resolution and tissue repair in a murine acute peritonitis model.

Highlights

The bidirectional communication between the immune and nervous system is important in regulating immune responses
Studies in a murine peritonitis model further show that both adrenergic nerves and repulsive guidance molecule A (RGM-A) synergistically reduce the level of inflammatory peritonitis, shorten the resolution interval, stimulate the local generation of pro-resolving lipid mediators, promote the clearance of apoptotic cells and stimulate tissue regeneration
We observed a significant reduction in the levels of the M1 markers and pro-inflammatory cytokines whereas the M2 markers and the anti-inflammatory cytokine were significantly increased (Fig. 1d), Together, these data indicate that RGM-A induced differentiation and polarization toward the M2 pro-healing and pro-resolving phenotype[13]

Summary

Introduction

The bidirectional communication between the immune and nervous system is important in regulating immune responses. We identified cholinergic nerve signaling to control the generation of immunoresolvents such as the neuronal guidance protein Netrin-1 and the SPMs during acute inflammation[10] In light of these accumulated findings, we decided to address the role of sympathetic nervous system (SNS) combined with the immunomodulatory actions of RGM-A in regulating resolution mechanism. Protein microarray analysis reflects suppression of NF-κB, activation of RICTOR signaling and PI3K/AKT signaling in peritoneal monocytes following the stimulation with RGM-A and/or β2AR agonist Together, these results show a new aspect of the neural-reflex circuit involving adrenergic nerves and RGM-A that controls key innate protective mechanisms in the resolution of acute inflammation and promotes tissue repair and regeneration

Methods

Results

Conclusion