Abstract
Human Campylobacter jejuni infections are emerging, and constitute a significant health burden worldwide. The ubiquitously expressed pituitary adenylate cyclase-activating polypeptide (PACAP) is well-known for its cell-protective and immunomodulatory effects. In our actual intervention study, we used an acute campylobacteriosis model and assessed the potential disease-alleviating effects of exogenous PACAP. Therefore, secondary abiotic IL-10−/− mice were perorally infected with C. jejuni and treated with synthetic PACAP38 intraperitoneally from day 2 until day 5 post-infection. Whereas PACAP did not interfere with the gastrointestinal colonization of the pathogen, mice from the PACAP group exhibited less severe clinical signs of C. jejuni-induced disease, as compared to mock controls, which were paralleled by alleviated apoptotic, but enhanced cell proliferative responses in colonic epithelia on day 6 post-infection. Furthermore, PACAP dampened the accumulation of macrophages and monocytes, but enhanced regulatory T cell responses in the colon, which were accompanied by less IFN-γ secretion in intestinal compartments in PACAP versus mock-treated mice. Remarkably, the inflammation-dampening properties of PACAP could also be observed in extra-intestinal organs, and strikingly, even the systemic circulation on day 6 post-infection. For the first time, we provide evidence that synthetic PACAP might be a promising candidate to combat acute campylobacteriosis and post-infectious sequelae.
Highlights
More than 20 years ago, the pituitary adenylate cyclase-activating polypeptide (PACAP) was identified in the hypothalamus and shown to stimulate adenylate cyclase activity in the pituitary gland [1]
Pathogens 2020, 9, 805 of the neuropeptide is not restricted to the nervous system, given that PACAP can be detected in peripheral organs belonging to the respiratory, endocrine, reproductive, and digestive tracts, and in distinct parts of the immune system
Both PACAP and vasoactive intestinal peptide (VIP) can bind to VPAC1 and VPAC2 receptors that are abundant on immune cells, such as macrophages and lymphocytes, whereas PAC1 constitutes a PACAP specific receptor which is expressed by macrophages as opposed to lymphocytes [3,4,5]
Summary
More than 20 years ago, the pituitary adenylate cyclase-activating polypeptide (PACAP) was identified in the hypothalamus and shown to stimulate adenylate cyclase activity in the pituitary gland [1]. Pathogens 2020, 9, 805 of the neuropeptide is not restricted to the nervous system, given that PACAP can be detected in peripheral organs belonging to the respiratory, endocrine, reproductive, and digestive tracts, and in distinct parts of the immune system Both PACAP and VIP can bind to VPAC1 and VPAC2 receptors that are abundant on immune cells, such as macrophages and lymphocytes, whereas PAC1 constitutes a PACAP specific receptor which is expressed by macrophages as opposed to lymphocytes [3,4,5]. Within one week following oral C. jejuni infection, secondary abiotic IL-10−/− mice developed acute enterocolitis characterized by wasting and bloody diarrhea [29] These acute inflammatory responses were not restricted to the intestinal tract, but could be observed in extra-intestinal organs and even in systemic compartments, and were all induced by C. jejuni LOS and mediated by activated. IL-10 for the very first time, applying C. jejuni infected secondary abiotic IL-10−/− mice
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