29
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction

          Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.

          Methods

          Antigen-induced arthritis (AIA) was established in IL-10KO mice and wild-type controls. Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies, we explored the regulation of inflammasome components. These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays.

          Results

          In AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores. Here, focal bone erosions were associated with increased tartrate-resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1β. When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components. Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1. In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis.

          Conclusions

          These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13075-014-0419-y) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 35

          • Record: found
          • Abstract: found
          • Article: not found

          IL-10 inhibits cytokine production by activated macrophages.

          IL-10 inhibits the ability of macrophage but not B cell APC to stimulate cytokine synthesis by Th1 T cell clones. In this study we have examined the direct effects of IL-10 on both macrophage cell lines and normal peritoneal macrophages. LPS (or LPS and IFN-gamma)-induced production of IL-1, IL-6, and TNF-alpha proteins was significantly inhibited by IL-10 in two macrophage cell lines. Furthermore, IL-10 appears to be a more potent inhibitor of monokine synthesis than IL-4 when added at similar concentrations. LPS or LPS- and IFN-gamma-induced expression of IL-1 alpha, IL-6, or TNF-alpha mRNA was also inhibited by IL-10 as shown by semiquantitative polymerase chain reaction or Northern blot analysis. Inhibition of LPS-induced IL-6 secretion by IL-10 was less marked in FACS-purified peritoneal macrophages than in the macrophage cell lines. However, IL-6 production by peritoneal macrophages was enhanced by addition of anti-IL-10 antibodies, implying the presence in these cultures of endogenous IL-10, which results in an intrinsic reduction of monokine synthesis after LPS activation. Consistent with this proposal, LPS-stimulated peritoneal macrophages were shown to directly produce IL-10 detectable by ELISA. Furthermore, IFN-gamma was found to enhance IL-6 production by LPS-stimulated peritoneal macrophages, and this could be explained by its suppression of IL-10 production by this same population of cells. In addition to its effects on monokine synthesis, IL-10 also induces a significant change in morphology in IFN-gamma-stimulated peritoneal macrophages. The potent action of IL-10 on the macrophage, particularly at the level of monokine production, supports an important role for this cytokine not only in the regulation of T cell responses but also in acute inflammatory responses.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Signaling by myeloid C-type lectin receptors in immunity and homeostasis.

            Myeloid cells are key drivers of physiological responses to pathogen invasion or tissue damage. Members of the C-type lectin receptor (CLR) family stand out among the specialized receptors utilized by myeloid cells to orchestrate these responses. CLR ligands include carbohydrate, protein, and lipid components of both pathogens and self, which variably trigger endocytic, phagocytic, proinflammatory, or anti-inflammatory reactions. These varied outcomes rely on a versatile system for CLR signaling that includes tyrosine-based motifs that recruit kinases, phosphatases, or endocytic adaptors as well as nontyrosine-based signals that modulate the activation of other pathways or couple to the uptake machinery. Here, we review the signaling properties of myeloid CLRs and how they impact the role of myeloid cells in innate and adaptive immunity.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

              To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.
                Bookmark

                Author and article information

                Contributors
                greenhillclaire1@gmail.com
                jonesgw6@cf.ac.uk
                nowellma@cf.ac.uk
                newtonzb@cf.ac.uk
                harveyak@cf.ac.uk
                moideenan1@cf.ac.uk
                collinsfl@cf.ac.uk
                bloomac@cf.ac.uk
                collr@tcd.ie
                avril.robertson@imb.uq.edu.au
                m.cooper@uq.edu.au
                rosasm@cf.ac.uk
                taylorpr@cf.ac.uk
                laoneill@tcd.ie
                humphreysir@cf.ac.uk
                williamsas@cf.ac.uk
                jonessa@cf.ac.uk
                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                30 August 2014
                2014
                : 16
                : 4
                Affiliations
                [ ]Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, Heath Park Campus, Cardiff, CF14 4XN Wales UK
                [ ]Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland
                [ ]Institute for Molecular Bioscience, The University of Queensland, St Lucia Campus, Brisbane 4072, QLD Australia
                Article
                419
                10.1186/s13075-014-0419-y
                4292830
                25175678
                b8b3bc5c-0c6a-442e-bde9-52128a84f3a0
                © Greenhill et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Orthopedics

                Comments

                Comment on this article