Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation

Abstract

Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co., 1999, Proc Natl Acad Sci USA, 2008, 105: 17949, Immunity, 44, 2016, 44: 463, N Engl J Med, 2011, 364: 656). Today, the resolution of inflammation is widely recognized as a cellular biochemically active process involving biosynthesis of a novel superfamily of endogenous chemical signals coined specialized pro‐resolving mediators (SPMs; Nature, 2014, 510:92). Herein, we review recent evidence, indicating a role for the vagus nerve and vagotomy in the regulation of lipid mediators. Vagotomy reduces pro‐resolving mediators, including the lipoxins, resolvins, protectins and maresins, delaying resolution in mouse peritonitis. Vagotomy also delays resolution of Escherichia coli infection in mice. Specifically, right vagus regulates peritoneal Group 3 innate lymphoid cell (ILC‐3) number and peritoneal macrophage responses with lipid mediator profile signatures with elevated pro‐inflammatory eicosanoids and reduced resolvins, including the novel protective immunoresolvent agonist protectin conjugate in tissue regeneration1 (PCTR1). Acetylcholine upregulates PCTR biosynthesis, and administration of PCTR1 to vagotomized mice restores tissue resolution and host responses to E. coli infections. Results obtained with human vagus ex vivo indicate that vagus can produce both pro‐inflammatory eicosanoids, such as prostaglandins and leukotrienes, as well as the SPM. Electrical stimulation of human vagus in vitro reduces both prostaglandins and leukotrienes and enhances resolvins and the other SPM. These results elucidate a host protective mechanism mediated by vagus stimulation of SPM that includes resolvins and PCTR1 to regulate myeloid antimicrobial functions and resolution of infection. Moreover, they define a new pro‐resolution of inflammation reflex operative in mice and human tissue that involves a vagus SPM circuit.

Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

“…Specialized pro-resolving mediators (SPMs) known as lipoxins, resolvins, protectins, and maresins are potent enzymatically-derived metabolites that orchestrate the resolution phase of inflammation and regeneration of damaged tissues [1][2][3][4] . SPMs are synthesized predominately from the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) 1 .…”

Protectin Conjugates in Tissue Regeneration 1 Restores Lipopolysaccharide-Induced Pulmonary Endothelial Glycocalyx Loss via ALX/SIRT1/NF-kappa B Axis

“…It was demonstrated that PCTR1 is increased to enhance macrophage recruitment and phagocytosis during the in ammation resolution phase [12] . Moreover, PCTR1 generation in peritoneal lavage is decreased in vagotomized mice, suggesting that PCTR1 is controlled by local vagal to improve in ammation resolution [13] . Our previous studies demonstrated that PCTR1 reduced LPS-induced in ammation in mice via regulating linoleic acid metabolism, and improved pulmonary edema uid clearance by activating the sodium channel and lymphatic drainage in LPS-triggered rat model [17,18] .…”

“…PCTR1 is identi ed and present in vivo before infection, and increases after LPS-induced in ammation, especially in in ammation resolution phrase [12] . Notably, PCTR1 not only enhances in ammation resolution by promoting macrophage efferocytosis and phagocytosis in infectious disease models but also improves tissue reparation [13,14] . However, the effect of PCTR1 on endothelial glycocalyx is still unde ned.…”

Bioelectronic medicine: an unexpected path to new therapies

“…Indeed, Seheran et al . provided evidence that signals via the vagus nerve regulate resolution of inflammation . The findings suggest that it may be possible to target the vagus nerve to accelerate resolution of inflammation and raises the question whether other nerves can be activated therapeutically to release pro‐resolving mediators and promote resolution of inflammation and tissue repair.…”

“…Disruption of signalling in the vagus nerve by vagotomy delayed resolution of peritonitis and bacterial infection in mice, and acetylcholine, a vagus nerve neurotransmitter, promoted biosynthesis of pro-resolving mediators. Indeed, Seheran et al provided evidence that signals via the vagus nerve regulate resolution of inflammation [9]. The findings suggest that it may be possible to target the vagus nerve to accelerate resolution of inflammation and raises the question whether other nerves can be activated therapeutically to release pro-resolving mediators and promote resolution of inflammation and tissue repair.…”