Emerging neuropeptide targets in inflammation: NPY and VIP

Abstract

The enteric nervous system (ENS), referred to as the "second brain," comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.

Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

“…Finally, MET and RET appear in nonoverlapping adult myenteric neuron populations, highlighting the need to define mechanisms restricting receptor tyrosine kinases (e.g., RET, NTRK3, and MET) to specific enteric neuron subtypes (Chalazonitis et al, , 2001Schuchardt et al, 1994;Heuckeroth et al, 1999;Uesaka et al, 2007Uesaka et al, , 2008.…”

“…MET should be disrupted in CGRP-expressing DRG neurons (Gascon et al, 2010) that might normally enhance mucosal repair (Takami et al, 2009;Engel et al, 2011Engel et al, , 2012Lee et al, 2012). MET inactivation in vagal neurons (Freem et al, 2010) could also increase severity of DSS-induced injury (Mazelin et al, 1999;Ghia et al, 2006Ghia et al, , 2007Van Der Zanden et al, 2009) since some vagal nuclei express Met (Caton et al, 2000;Wu and Levitt, 2013). Distinguishing between these possibilities is not straightforward, but these data fit with an emerging literature suggesting neuronal activity regulates intestinal epithelial progenitor proliferation and barrier function (Bjerknes and Cheng, 2001;Nezami and Srinivasan, 2010;Hitch et al, 2012;Sharkey and Savidge, 2014).…”

“…Indeed, many ENS transmitters affect bowel inflammation and injury, including CGRP (Eysselein et al, 1992;Wang et al, 2006;Ramachandran et al, 2013), serotonin (Bischoff et al, 2009;, neuropeptide Y, VIP (Chandrasekharan et al, 2013), and substance P (Landau et al, 2007), as do enteric glia (Bush et al, 1998;Savidge et al, 2007), enteric neuron density , and toll-like receptor 2 (Brun et al, 2013). Our data reinforce this literature and suggest that new therapeutic strategies to treat or prevent intestinal motility or bowel inflammatory diseases may be targeted to the nervous system instead of the immune system.…”

“…Some signals governing ENS development and maintenance are known (Sasselli et al, 2012;Lake and Heuckeroth, 2013;Obermayr et al, 2013), but it is unclear how diverse neuronal populations are established or what factors support most enteric neurons after birth. Trophic factors that affect ENS development, maintenance, and function include glial cell line-derived neurotrophic factor (GDNF; Sánchez et al, 1996;Treanor et al, 1996;Chalazonitis et al, 1998;Hearn et al, 1998;Heuckeroth et al, 1998), neurturin (Heuckeroth et al, , 1999, nerve growth factor (NGF;Mulholland et al, 1994), brain derived neurotrophic factor (Grider et al, 1997b;Boesmans et al, 2008), ciliary neurotrophic factor (Grider et al, 1997a;Chalazonitis et al, 2001;Schäfer et al, 2003), and neurotrophin-3 (Chalazonitis et al, , 1998(Chalazonitis et al, , 2001). We hypothesized, that hepatocyte growth factor (HGF) and its receptor MET might also be important because HGF supports spinal motor neurons (Ebens et al, 1996), dorsal root ganglion (DRG) subtypes (Maina et al, 1997), retinal ganglion cells (Tönges et al, 2011), and hippocampal neurons (Lim and Walikonis, 2008).…”

Neuronal pathways in tendon healing and tendinopathy - update

“…The non-vascular distribution of VIP would seem to comply with an anti-inflammatory effect in the periphery ( Figure 1C) (69)(70)(71). The strong anti-inflammatory role of VIP has been suggested to act through inhibition of T cell proliferation and migration (64,(71)(72)(73).…”