Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.

The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs.

Objective The aim of this study was to analyze both the constitutive and induced expression and function of double‐stranded RNA (dsRNA; Toll‐like receptor 3 [TLR‐3], retinoic acid–inducible gene I [RIG‐I], and melanoma differentiation‐associated gene 5 [MDA5]) and single‐stranded RNA (ssRNA; TLR‐7) receptors in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS), by studying the transcription factors involved and the subsequent effects on antiviral interferon‐β (IFNβ), the proinflammatory CXCL8 chemokine, and matrix metalloproteinase 3 (MMP‐3). An additional goal was to study the effect of vasoactive intestinal peptide (VIP). Methods The expression of TLR‐3, TLR‐7, RIG‐I, and MDA5 in cultured FLS was studied by reverse transcription–polymerase chain reaction (RT‐PCR), enzyme‐linked immunosorbent assay (ELISA), immunofluorescence, and Western blotting. Transcription factors were studied using the ELISA‐based TransAM transcription factor kit. The expression of IFNβ, CXCL8 (interleukin‐8), and MMP‐3 was analyzed by RT‐PCR and ELISA. Results FLS expressed TLR‐3, TLR‐7, RIG‐I, and MDA5. The expression of TLR‐3 and RIG‐I was higher in RA FLS, while the expression of TLR‐7 and MDA5 was higher in OA FLS. Stimulation with poly(I‐C) induced the activation of IFN regulatory factor 3 (IRF‐3), NF‐κB, and activator protein 1 (AP‐1) c‐Jun as well as the subsequent production of IFNβ, CXCL8, and MMP‐3. VIP reduced the activation of IRF‐3 and the production of IFNβ in both OA and RA FLS. Imiquimod induced the activation of NF‐κB, AP‐1 c‐Fos, and AP‐1 c‐Jun and the synthesis of CXCL8 and MMP‐3. VIP significantly diminished MMP‐3 production only in imiquimod‐treated RA FLS. Conclusion The results of this study revealed a prominent function of FLS in the recognition of both dsRNA and ssRNA, which may be present in the joint microenvironment. This study also advances the healing function of the endogenous neuroimmune peptide VIP, which inhibited TLR‐3–, RIG‐I–, MDA5‐, and TLR‐7–mediated stimulation of antiviral, proinflammatory, and joint destruction mediators.

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP’s discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

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.

Several studies in humans indicate the implication of T_h17 cells in RA. Therapies targeting their pathogenicity, as well as their plasticity to the T_h17/1 phenotype, could ameliorate the progression of the pathology. The neuroendocrine environment has a major impact on the differentiation of lymphoid cells. VIP is present in the microenvironment of the joint, and its known therapeutic effects are supported by several studies on RA. We examine the ability of VIP to modulate the differentiation of T_h17 cells. Peripheral blood CD4⁺CD45RO⁺ T cells from HD and eRA patients were expanded under T_h17-polarizing conditions in the presence of TGF-β. After 7 days, the higher IL-17A, IL-21, and IL-9 levels and lower IL-22 levels indicate the nonpathogenic profile for T_h17 cells in HD. In contrast, T_h17 cells from eRA patients produced significantly more IL-22 and IFN-γ, and these cells show a more T_h17/1 profile, indicating a pathogenic phenotype. Interestingly, when VIP was present in the T_h17 conditioned medium, increased levels of IL-10 and IL-9 were detected in HD and eRA patients. VIP also reduced the levels of IL-22 in eRA patients. These data suggest that VIP reduces the pathogenic profile of the T_h17-polarized cells. This effect was accompanied by an increased in the T_reg/T_h17 profile, as shown by the increase levels of Foxp3. In conclusion, this report addresses a novel and interesting question on the effect of VIP on human T_h17 cells and adds clinical relevance by analyzing, in parallel, HD and eRA patients.