VIP impairs acquisition of the macrophage proinflammatory polarization profile

Abstract

This study tested the hypothesis that vasoactive intestinal peptide (VIP) is able to modify the macrophage inflammatory profile, thus supporting its therapeutic role in autoimmune diseases. Macrophages are innate immune cells that display a variety of functions and inflammatory profiles in response to the environment that critically controls their polarization. Deregulation between the pro- and anti-inflammatory phenotypes has been involved in different pathologies. Rheumatoid arthritis (RA) is an autoimmune disease, in which macrophages are considered central effectors of synovial inflammation, displaying a proinflammatory profile. VIP is a pleiotropic neuropeptide with proven anti-inflammatory actions. As modulation of the macrophage phenotype has been implicated in the resolution of inflammatory diseases, we evaluated whether VIP is able to modulate human macrophage polarization. In vitro-polarized macrophages by GM-CSF (GM-MØ), with a proinflammatory profile, expressed higher levels of VIP receptors, vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2, respectively), than macrophages polarized by M-CSF (M-MØ) with anti-inflammatory activities. RA synovial macrophages, according to their GM-CSF-like polarization state, expressed both VPAC1 and VPAC2. In vitro-generated GM-MØ exposed to VIP exhibited an up-regulation of M-MØ gene marker expression, whereas their proinflammatory cytokine profile was reduced in favor of an anti-inflammatory function. Likewise, in GM-MØ, generated in the presence of VIP, VIP somehow changes the macrophages physiology profile to a less-damaging phenotype. Therefore, these results add new value to VIP as an immunomodulatory agent on inflammatory diseases.

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

“…VIP expression has also been described in human eosinophils [30] and in eosinophils of granulomatous lesions induced by infection with Schistosomiasis mansoni [31]. We reported that neither M1 nor M2 human macrophages express transcripts of VIP [32]. Concerning cells of a lymphoid lineage, in the 1990s, our team reported, for the first time, the synthesis and secretion of VIP in murine T and B lymphocytes [33][34][35].…”

“…Upregulated levels of pro-inflammatory mediators, including TNF-α, IL-6, and CXCL8 and CCL2 chemokines, in polyclonally stimulated peripheral blood lymphocytes from RA patients were reduced after treatment with VIP [167]. Furthermore, regarding its effects on macrophages, VIP was able to impair the acquisition of the pro-inflammatory polarization profile described for macrophages in RA synovium, favoring instead an anti-inflammatory phenotype [32]. Additionally, the involvement of VIP in the modulation of Th subsets has been extensively studied, as previously detailed.…”

Dissecting the microenvironment around biosynthetic scaffolds in murine skin wound healing

“…Among them, one subpopulation showed increased expression of genes associated with anti-inflammatory macrophages, such as Ccl8, Folr2, C1qa and Mrc1, and was named anti-inflammatory macrophages (AIM). (35,36) Another subset characterized by elevated expression of pro-inflammatory genes (Ptgs2, Ccl3, Inhba, Nos2) was named pro-inflammatory macrophages (PIM) (37,38). The monocyte subset (Mono) was characterized by increased expression of genes like Ly6c2 and Plac8 (Fig.…”

Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease

“…VIP inhibits the production of proinflammatory cytokines such as tumor necrosis factor α (TNFα), IL-6, IL-12, iNOS, and promotes the production anti-inflammatory cytokines such as IL-10[ 148 - 153 ]. VIP also inhibits the transcription factors AP-1, nuclear factor-κB (NFκB), CREB, and IRF-1[ 142 , 147 , 153 , 154 ], and impairs the acquisition of the macrophage proinflammatory polarization profile[ 155 ].…”