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.
Nonresolving inflammation, a hallmark of underlying severe inflammatory processes such as sepsis, acute respiratory distress syndrome and multiple organ failure is a major cause of admission to the intensive care unit and high mortality rates. Many survivors develop new functional limitations and health problems, and in cases of sepsis, approximately 40% of patients are rehospitalized within three months. Over the last few decades, better treatment approaches have been adopted. Nevertheless, the lack of knowledge underlying the complex pathophysiology of the inflammatory response organized by numerous mediators and the induction of complex networks impede curative therapy. Thus, increasing evidence indicates that resolution of an acute inflammatory response, considered an active process, is the ideal outcome that leads to tissue restoration and organ function. Many mediators have been identified as immunoresolvents, but only a few have been shown to contribute to both the initial and resolution phases of severe systemic inflammation, and these agents might finally substantially impact the therapeutic approach to severe inflammatory processes. In this review, we depict different resolution mediators/immunoresolvents contributing to resolution programmes specifically related to life-threatening severe inflammatory processes.
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