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

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.

Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

“…. The gating strategy can be found in SI Appendix, S13 (45). For therapeutic treatment with SH42, peritonitis was initiated as described above using 1 mL of a zyA solution.…”

“…Targeted LM Analysis. Targeted LM analysis was carried out as described elsewhere (45). Further details are available in SI Appendix, S16 and Table S1, and raw data are available in Dataset S6.…”

“…As a next step in integrating our results with inflammation resolution, we focused on monocyte differentiation and MΦ phenotypes as both processes are crucial for inflammation resolution. As cell shape and MΦ phenotype are correlated (44), we carried out cell shape analysis assessing monocyte differentiation toward the M1 or M2 phenotype (45). As can be seen in Fig.…”

<p>Novel Resolution Mediators of Severe Systemic Inflammation</p>

“…Thus, a recent report highlighted a novel facet of inflammatory reflexes in that adrenergic nerve fibres of the sympathetic nervous system together with the NGP Repulsive Guidance Molecule A (RGM-A) regulate the resolution of acute inflammation and promote tissue regeneration (Figure 2). 47 The protein RGM-A was shown to substantially influence the initial phase of acute inflammation and the pathobiology of autoimmune encephalomyelitis. 43,48,49 In a study by Körner and colleagues, 47 Notes: The adrenergic nerve together with the neuronal guidance protein RGM-A activate resolution programmes.…”

“…47 The protein RGM-A was shown to substantially influence the initial phase of acute inflammation and the pathobiology of autoimmune encephalomyelitis. 43,48,49 In a study by Körner and colleagues, 47 Notes: The adrenergic nerve together with the neuronal guidance protein RGM-A activate resolution programmes. RGM-A enhances the expression of the β2 adrenergic receptor (β2AR) on human MΦs, and activation of β2AR, in turn, increases RGM-A expression on MΦs.…”