Abstract
The neuropeptide Pituitary adenylate cyclase-activating polypeptide (PACAP) is well-known for its important functions in immunity and inflammation. Data regarding anti-inflammatory properties of PACAP in the intestinal tract are limited, however. In our present preclinical intervention study we addressed whether PACAP treatment could alleviate experimental subacute ileitis mimicking human gut microbiota conditions. Therefore, secondary abioitic mice were subjected to human fecal microbiota transplantation (FMT) and perorally infected with low-dose Toxoplasma gondii to induce subacute ileitis on day 0. From day 3 until day 8 post-infection, mice were either treated with synthetic PACAP38 or placebo. At day 9 post-infection, placebo, but not PACAP treated mice exhibited overt macroscopic sequelae of intestinal immunopathology. PACAP treatment further resulted in less distinct apoptotic responses in ileal and colonic epithelia that were accompanied by lower T cell numbers in the mucosa and lamina propria and less secretion of pro-inflammatory cytokines in intestinal ex vivo biopsies. Notably, ileitis-associated gut microbiota shifts were less distinct in PACAP as compared to placebo treated mice. Inflammation-ameliorating effects of PACAP were not restricted to the intestines, but could also be observed in extra-intestinal including systemic compartments as indicated by lower apoptotic cell counts and less pro-inflammatory cytokine secretion in liver and lungs taken from PACAP treated as compared to placebo control mice, which also held true for markedly lower serum TNF and IL-6 concentrations in the former as compared to the latter. Our preclinical intervention study provides strong evidence that synthetic PACAP alleviates subacute ileitis and extra-intestinal including systemic sequelae of T cell-driven immunopathology. These findings further support PACAP as a novel treatment option for intestinal inflammation including inflammatory bowel diseases (IBD).
Highlights
The Pituitary adenylate cyclase-activating polypeptide (PACAP) could be first identified in the hypothalamus exerting adenylate cyclase stimulating activity within the pituitary gland [1]
In the present preclinical intervention study we addressed whether therapeutic application of synthetic PACAP dampened pro-inflammatory responses in intestinal and extra-intestinal including systemic compartments of mice with a human gut microbiota suffering from subacute ileitis
Our previous work revealed that synthetic PACAP application starting prior acute ileitis induction ameliorated intestinal as well as extraintestinal sequelae of peroral high-dose T. gondii infection in a time-of-treatment dependent manner [17] that is characterized by a T cell-driven pro-inflammatory cytokine storm with fatal outcome within 1 week [14, 15]
Summary
The Pituitary adenylate cyclase-activating polypeptide (PACAP) could be first identified in the hypothalamus exerting adenylate cyclase stimulating activity within the pituitary gland [1]. PACAP expression can be found in many peripheral organs within the reproductive, respiratory, endocrine and digestive system as well as in lymphoid compartments including immune cells [2]. PACAP is able to bind to VPAC1, VPAC2, and PAC1 receptors on innate immune cells including macrophages and lymphocytes [3–5]. Given its virtual ubiquitous expression, PACAP presents with a variety of cyto-protective properties including anti-inflammatory and anti-apoptotic effects [5, 6]. In experimental models of encephalomyelitis and arthritis, for instance, distinct anti-inflammatory effects following exogenous PACAP application have been demonstrated [7, 8]. Data regarding inflammation-ameliorating properties of synthetic PACAP in the gastrointestinal tract are limited, . PACAP−/− mice suffered from more severe acute colitis following dextran sodium sulfate (DSS) challenge as compared to wildtype counterparts [9, 10]
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