Vagal Regulation of Group 3 Innate Lymphoid Cells and the Immunoresolvent PCTR1 Controls Infection Resolution

Abstract

Summary Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious-inflammation without unwanted side effects. Herein, we found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right vagus decreased peritoneal Group 3 innate lymphoid cell (ILC3) numbers and altered peritoneal macrophage responses. Vagotomy resulted in an inflammatory peritoneal lipid mediator profile characterized by reduced concentrations of resolvins, including the protective immunoresolvent PCTR1, along with elevated inflammation-initiating eicosanoids. We found that acetylcholine upregulated the PCTR biosynthetic pathway in ILC3s. Administration of PCTR1 or ILC3s to vagotomised mice restored tissue resolution tone and host responses to E. coli infections. Together these findings elucidate a host protective mechanism mediated by ILC3-derived pro-resolving circuit, including PCTR1, that is controlled by local neuronal output to regulate tissue resolution tone and myeloid cell responses.

Molecular and Functional Neuroscience in Immunity

“…Experiments utilizing vagotomy in a mouse model of zymosan-induced peritonitis indicated that vagus nerve cholinergic signaling promotes resolution processes in the lungs and abdominal tissues, mediated by netrin-1, an axonal guidance molecule and newly identified proresolving molecule (109). Vagus nerve cholinergic signaling was also implicated in enhancing inflammation resolution in response to bacterial infection (110). This neural control affects peritoneal group 3 innate lymphoid cells and the release of the protective resolvent molecule PCTR1 (110).…”

“…Vagus nerve cholinergic signaling was also implicated in enhancing inflammation resolution in response to bacterial infection (110). This neural control affects peritoneal group 3 innate lymphoid cells and the release of the protective resolvent molecule PCTR1 (110). These findings highlighting a role of the efferent vagus nerve in inflammation resolution in addition to its anti-inflammatory control suggest that the vagus nerve may function as an integrator of inflammatory stages.…”

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

“…Dysregulation in pro-resolving mediator signaling is associated with unresolved chronic inflammation, which drives pathology in a myriad of diseases (Serhan, 2014; Nathan and Ding, 2010). Recent findings indicate that inflammation resolution is regulated by neural signaling along the vagus nerve (Mirakaj et al, 2014; Dalli et al, 2017). Experiments with vagotomy (unilateral cervical) in a mouse model of zymosaninduced peritonitis revealed that vagus nerve signals control the lung and abdominal tissue expression of netrin-1, an axonal guidance molecule, rediscovered as an innate immune system pro-resolving mediator (Mirakaj et al, 2014).…”

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

“…Continued investigation along these lines permitted elucidation of three separate pathways, coined MCTRs, PCTRs and RCTRs. The stereochemistry of MCTR1, MCTR2 and MCTR3 and PCTR1 (Dalli et al, 2016a; Ramon et al, 2016) are established (Figure 2), and they are produced in mouse lymphoid tissues and in infectious inflammatory exudates as well as in specific human tissues (Dalli et al, 2017a). …”