An Overview of VPAC Receptors in Rheumatoid Arthritis: Biological Role and Clinical Significance

Abstract

The axis comprised by the Vasoactive Intestinal Peptide (VIP) and its G protein-coupled receptors (GPCRs), VPAC1, and VPAC2, belong to the B1 family and signal through Gs or Gq proteins. VPAC receptors seem to preferentially interact with Gs in inflammatory cells, rather than Gq, thereby stimulating adenylate cyclase activity. cAMP is able to trigger various downstream pathways, mainly the canonical PKA pathway and the non-canonical cAMP-activated guanine nucleotide exchange factor (EPAC) pathway. Classically, the presence of VPACs has been confined to the plasma membrane; however, VPAC1 location has been described in the nuclear membrane in several cell types such as activated Th cells, where they are also functional. VPAC receptor signaling modulates a number of biological processes by tipping the balance of inflammatory mediators in macrophages and other innate immune cells, modifying the expression of TLRs, and inhibiting MMPs and the expression of adhesion molecules. Receptor signaling also downregulates coagulation factors and acute-phase proteins, promotes Th2 over Th1, stimulates Treg abundance, and finally inhibits a pathogenic Th17 profile. Thus, the VIP axis signaling regulates both the innate and adaptive immune responses in several inflammatory/autoimmune diseases. Rheumatoid arthritis (RA) is a complex autoimmune disease that develops on a substrate of genetically susceptible individuals and under the influence of environmental factors, as well as epigenetic mechanisms. It is a heterogeneous disease with different pathogenic mechanisms and variable clinical forms between patients with the same diagnosis. The knowledge of VIP signaling generated in both animal models and human ex vivo studies can potentially be translated to clinical reality. Most recently, the beneficial effects of nanoparticles of VIP self-associated with sterically stabilized micelles have been reported in a murine model of RA. Another novel research area is beginning to define the receptors as biomarkers in RA, with their expression levels shown to be associated with the activity of the disease and patients-reported impairment. Therefore, VPAC expression together VIP genetic variants could allow patients to be stratified at the beginning of the disease with the purpose of guiding personalized treatment decisions.

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

“…Most of them were created by modifying endogenous peptides and displayed different affinities and selectivities, with the first descriptions unable to differentiate between the two receptors [56][57][58]. Selective agonists for VPAC1 receptor have been generated, such as [K 15 , R 16 , L 27 ]VIP(1-7)/GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) [59], [Ala 11,22,28 ]VIP [60], [L 22 ]VIP [61], [R 16 ]PACAP(1-23) [62], and LBT-3393 [63]. A selective antagonist is also available: PG97-269 [64].…”

“…Synthesized by neurons and endocrine and immune cells, VIP is involved in the control of both innate and adaptive immune responses [4][5][6]. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by two G-protein-coupled receptors (VPAC1, VPAC2) [7][8][9][10][11][12].…”

Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis

“…Joint tissues are sources of bioactive neuropeptides, such as neuropeptide Y, pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide (VIP) that induces changes in the cell metabolism in degenerative conditions such as OA [ 19 ]. VIP and its G protein-coupled receptors (GPCRs), VPAC1, and VPAC2, form a signaling axis that modulates both the innate and acquired immunity in several inflammatory/autoimmune diseases, including OA [ 20 , 21 ]. VIP sources in the joint comprise both nerve fibers of the sympathetic nervous system and a cellular origin, including lymphocytes and SF from OA and RA patients [ 20 , 21 , 22 ].…”

Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells

“…First, VIP inhibits the production of the Th1-related cytokine, IL-12[ 45 ]. Second, VIP was reported to induce the expression of CD86 in resting mouse DCs, which played an important role in the development of Th2 cells[ 46 ]. Third, VIP inhibited CD95 (FasL) and granulase B-mediated apoptosis of mouse T2 cells but not of Th1 effector cells[ 47 ].…”