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

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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.

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Most cited references 35

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IL-10 inhibits cytokine production by activated macrophages.

D Fiorentino, A Zlotnik, T R Mosmann … (1991)

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.

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

Kristi Silver, Francis X Burch, X Chevalier … (2009)

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.

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Author and article information

Contributors

Claire J Greenhill: greenhillclaire1@gmail.com

Gareth W Jones: jonesgw6@cf.ac.uk

Mari A Nowell: nowellma@cf.ac.uk

Zarabeth Newton: newtonzb@cf.ac.uk

Ann K Harvey: harveyak@cf.ac.uk

Abdul N Moideen: moideenan1@cf.ac.uk

Fraser L Collins: collinsfl@cf.ac.uk

Anja C Bloom: bloomac@cf.ac.uk

Rebecca C Coll: collr@tcd.ie

Avril AB Robertson: avril.robertson@imb.uq.edu.au

Matthew A Cooper: m.cooper@uq.edu.au

Marcela Rosas: rosasm@cf.ac.uk

Philip R Taylor: taylorpr@cf.ac.uk

Luke A O’Neill: laoneill@tcd.ie

Ian R Humphreys: humphreysir@cf.ac.uk

Anwen S Williams: williamsas@cf.ac.uk

Simon A Jones: jonessa@cf.ac.uk

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 30 August 2014

Publication date (Print): 2014

Volume: 16

Issue: 4

Electronic Location Identifier: 419

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

Publisher ID: 419

DOI: 10.1186/s13075-014-0419-y

PMC ID: 4292830

PubMed ID: 25175678

SO-VID: b8b3bc5c-0c6a-442e-bde9-52128a84f3a0

License:

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.

History

Date received : 29 November 2013

Date accepted : 1 August 2014

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ScienceOpen disciplines: Orthopedics

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ScienceOpen disciplines: Orthopedics

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

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Abstract

Introduction

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Orthopedics

Most cited references 35

IL-10 inhibits cytokine production by activated macrophages.

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

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

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Cited by 44

Most referenced authors 503