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

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

Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

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

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

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

The Adipokine network in rheumatic joint diseases

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 Northern ROSAT All-Sky (NORAS) Galaxy Cluster Survey I: X-ray Properties of Clusters Detected as Extended X-ray Sources

In the construction of an X-ray selected sample of galaxy clusters for cosmological studies, we have assembled a sample of 495 X-ray sources found to show extended X-ray emission in the first processing of the ROSAT All-Sky Survey. The sample covers the celestial region with declination $\delta \ge 0\deg$ and galactic latitude $|b_{II}| \ge 20\deg$ and comprises sources with a count rate $\ge 0.06$ counts s$^{-1}$ and a source extent likelihood of 7. In an optical follow-up identification program we find 378 (76%) of these sources to be clusters of galaxies. ...Comment: 61 pages; ApJS in press; fixed bug in table file; also available at (better image quality) http://www.xray.mpe.mpg.de/theorie/NORAS

La autoestima y su relación con la ansiedad social y las habilidades sociales

Este trabajo examina la autoestima y sus dimensiones utilizando la “Escala Janis-Field de sentimientos de inadecuación-Revisada” (RJFFIS) y la “Escala Rosenberg de autoestima” (RSES) en una muestra mayoritariamente universitaria (n= 826). Analizamos su relación con la ansiedad social (AS) y las habilidades sociales (HHSS), evaluadas con el “Cuestionario de ansiedad social para adultos” (CASO), el “Cuestionario de habilidades sociales” (CHASO) y el “Inventario de asertividad de Rathus” (RAS). La solución heptafactorial de la RJFFIS explica el 59, 65% de la varianza común y apoya un concepto multifactorial de la autoestima, incluyendo facetas que tienen que ver con la apariencia y habilidades físicas, relaciones sociales y habilidades académicas o laborales. Las correlaciones moderadas con la RSES apoyan la validez convergente de la RJFFIS. Por otra parte, la autoestima se relaciona de forma moderada con la AS y las HHSS. Los sujetos con alta AS muestran una autoestima significativamente más baja que aquellos con baja AS y lo opuesto ocurre respecto a las HHSS. Existen diferencias de sexo en cuanto a la autoestima, mostrando los hombres puntuaciones más altas que las mujeres. Estos resultados sustentan la naturaleza multidimensional de la autoestima y la necesidad de investigar su papel en las áreas tanto de la AS como de las HHSS. This paper examines self-esteem and its dimensions using the Revised Janis-Field Feelings of Inadequacy Scale (RJFFIS) and the Rosenberg Self-Esteem Scale (RSES) in a sample comprising mostly university undergraduates (n= 826). We analyzed their relationship with social anxiety (SA) and social skills (SS), assessed with the Social Anxiety Questionnaire for adults (SAQ), the Social Skills Questionnaire (CHASO) and the Rathus Assertiveness Schedule (RAS). The hepta-factorial solution for the RJFFIS explains 59.65% of the common variance and supports a multifactorial concept of self-esteem, including facets that have to do with physical appearance and abilities, social relationships, and academic or work skills. The moderate correlations with the RSES support the convergent validity of the RJFFIS. On the other hand, self-esteem is moderately related to SA and SS. Subjects with high SA show significantly lower self-esteem than those with a low SA and the opposite occurs regarding SS. There are gender differences in terms of self-esteem, with men showing higher scores than women. These results support the multidimensional nature of self-esteem and the need to investigate its role in the areas of both SA and SS

The anti-inflammatory mediator, vasoactive intestinal peptide, modulates the differentiation and function of Th Subsets in rheumatoid arthritis

Genetic background, epigenetic modifications, and environmental factors trigger autoimmune response in rheumatoid arthritis (RA). Several pathogenic infections have been related to the onset of RA and may cause an inadequate immunological tolerance towards critical self-antigens leading to chronic joint inflammation and an imbalance between different T helper (Th) subsets. Vasoactive intestinal peptide (VIP) is a mediator that modulates all the stages comprised between the arrival of pathogens and Th cell differentiation in RA through its known anti-inflammatory and immunomodulatory actions. This “neuroimmunopeptide” modulates the pathogenic activity of diverse cell subpopulations involved in RA as lymphocytes, fibroblast-like synoviocytes (FLS), or macrophages. In addition, VIP decreases the expression of pattern recognition receptor (PRR) such as toll-like receptors (TLRs) in FLS from RA patients. These receptors act as sensors of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) connecting the innate and adaptive immune system. Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells. Finally, VIP regulates the plasticity between theses subsets. In this review, we provide an overview of VIP effects on the aforementioned features of RA pathology

Activation of Th lymphocytes alters pattern expression and cellular location of VIP receptors in healthy donors and early arthritis patients

Vasoactive Intestinal Peptide (VIP) is an important immunomodulator of CD4+ cells in normal and pathological conditions, which exerts its anti-infammatory and immunomodulatory actions through VPAC receptors, VPAC1 and VPAC2. Only a decrease in the expression of VPAC1 mRNA on Th cells upon activation has been reported. Thus, the deepening in the knowledge of the behavior of these receptors may contribute to the design of new therapies based on their activation and/or blockade. In this study, we describe the expression pattern, cellular location and functional role of VIP receptors during the activation of human Th cells in healthy conditions and in early arthritis (EA). The protein expression pattern of VPAC1 did not change with the activation of Th lymphocytes, whereas VPAC2 was up-regulated. In resting cells, VPAC1 was located on the plasma membrane and nucleus, whereas it only appeared in the nucleus in activated cells. VPAC2 was always found in plasma membrane location. VIP receptors signaled through a PKA-dependent pathway in both conditions, and also by a PKAindependent pathway in activated cells. Both receptors exhibit a potent immunomodulatory capacity by controlling the pathogenic profle and the activation markers of Th cells. These results highlight a novel translational view in infammatory/autoimmune diseases