Immunomodulatory Effects of the Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide in Acute Toxoplasmosis

Caio Andreeta Figueiredo,Markus M Heimesaat,Gabor K Toth,Nishith Gupta,Johannes Steffen,Henning Peter Düsedau,Ildiko Rita Dunay,Dora Reglodi,Miklos Pal Dunay

doi:10.3389/fcimb.2019.00154

Abstract

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is an endogenous neuropeptide with distinct functions including the regulation of inflammatory processes. PACAP is able to modify the immune response by directly regulating macrophages and monocytes inhibiting the production of inflammatory cytokines, chemokines and free radicals. Here, we analyzed the effect of exogenous PACAP on peripheral immune cell subsets upon acute infection with the parasite Toxoplasma gondii (T. gondii). PACAP administration was followed by diminished innate immune cell recruitment to the peritoneal cavity of T. gondii-infected mice. PACAP did not directly interfere with parasite replication, instead, indirectly reduced parasite burden in mononuclear cell populations by enhancing their phagocytic capacity. Although proinflammatory cytokine levels were attenuated in the periphery upon PACAP treatment, interleukin (IL)-10 and Transforming growth factor beta (TGF-β) remained stable. While PACAP modulated VPAC1 and VPAC2 receptors in immune cells upon binding, it also increased their expression of brain-derived neurotrophic factor (BDNF). In addition, the expression of p75 neurotrophin receptor (p75NTR) on Ly6Chi inflammatory monocytes was diminished upon PACAP administration. Our findings highlight the immunomodulatory effect of PACAP on peripheral immune cell subsets during acute Toxoplasmosis, providing new insights about host-pathogen interaction and the effects of neuropeptides during inflammation.

Highlights

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino-acid neuropeptide in the glucagon superfamily together with secretin and vasoactive intestinal peptide (VIP) (Sherwood et al, 2000)
As our previous studies demonstrated the critical importance of myeloid cells in the control of T. gondii infection (Dunay et al, 2010; Biswas et al, 2015; Mohle et al, 2016), we analyzed the mononuclear compartment based on the expression of CD11b and Ly6G
We investigated the immunomodulatory effect of PACAP on innate immune cells isolated from the peritoneal cavity during experimental acute T. gondii infection

Summary

INTRODUCTION

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino-acid neuropeptide in the glucagon superfamily together with secretin and vasoactive intestinal peptide (VIP) (Sherwood et al, 2000). Elimination of T. gondii involves a complex recruitment of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) (Zhao et al, 2009; Fentress et al, 2010). After infection, these host defense factors are known to accumulate in the membrane of the parasitophorous vacuole (PV) culminating with its disruption and parasite elimination (Macmicking, 2012). We recently showed the innate immune response and the influence of neurotrophin signaling upon T. gondii-induced neuroinflammation. We detected altered expression of BDNF and p75NTR in peritoneal cells, pointing toward the contribution of PACAP to the parasite elimination and neurotrophin signaling in immune cells upon acute Toxoplasmosis

MATERIALS AND METHODS

RESULTS

DISCUSSION