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IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis

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Abstract

Objective

To investigate the role of IL-33 in gouty arthritis.

Material

174 Balb/c (wild-type) and 54 ST2−/− mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels.

Methods

Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM.

Results

Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1β and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1β and TNF-α, and BMDMs from ST2−/− showed reduced levels of these cytokines after stimulus with MSU crystals.

Conclusion

IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.

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Acknowledgements

Grants that supported the present study were from the National Council for Scientific and Technological Development (CNPq, Brazil); Department of Science and Technology from the Science, Technology and Strategic Inputs Secretariat of the Ministry of Health (Decit/SCTIE/MS, Brazil) intermediated by CNPq with support of Araucária Foundation and State Health Secretariat, Paraná (SESA‐PR, Brazil; PPSUS Grant Agreement 041/2017, protocol 48.095); Funding Authority for Studies and Projects and State Secretariat of Science, Technology and Higher Education (MCTI/FINEP/CT‐INFRA‐PROINFRA, Brazil; Grant agreements 01.12.0294.00 and 01.13.0049.00); Programa de Apoio a Grupos de Excelência (PRONEX) grant supported by SETI/Araucária Foundation and MCTI/CNPq; and Paraná State Government (Agreement 014/2017, protocol 46.843); Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; finance code 001); National Institute of Science and Technology in Dengue and Host-microorganism Interaction (INCT dengue), which is a program sponsored by CNPq and the Minas Gerais Foundation for Science (FAPEMIG, Brazil); São Paulo Research Foundation under grant agreement 2013/08216-2 (Center for Research in Inflammatory Disease). We also thank the support of Central Multiusuário de Laboratórios de Pesquisa from Londrina State University (CMLP‐UEL).

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Authors and Affiliations

  1. Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, Londrina, Brazil

    Victor Fattori, Larissa Staurengo-Ferrari, Tiago H. Zaninelli & Waldiceu A. Verri Jr

  2. Department of Pharmaceutical Science, Londrina State University, Londrina, Brazil

    Rubia Casagrande

  3. Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Rene D. Oliveira & Paulo Louzada-Junior

  4. Department of Pharmacology, Center for Research in Inflammatory Diseases, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Thiago M. Cunha, Jose C. Alves-Filho & Fernando Q. Cunha

  5. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Mauro M. Teixeira & Flavio A. Amaral

  6. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, PR 445, KM 380, PO Box 10.011, Londrina, Parana, 86057-970, Brazil

    Waldiceu A. Verri Jr

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  1. Victor Fattori
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Correspondence to Waldiceu A. Verri Jr.

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There is no conflict of interest to be declared.

Ethical approval

All animal experiments were conducted in accordance with animal care and handling procedures of the International Association for Study of Pain (IASP) and with the approval Londrina State University Ethics Committee on Animal Research and Welfare named CEUA-UEL (Approval Number 2205.2016.39). All patients were recruited at the Division of Rheumatology, Hospital das Clínicas, Ribeirão Preto Medical School (HC-FMRP, São Paulo, Brazil), and presented clinical or laboratory variables that fulfilled the criteria for osteoarthritis or gouty arthritis. All patients were informed about the aims of the study and provided written consent before participating. The Human Ethics Committee of the FMRP approved this study (Approval Number 4971/2012).

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Fattori, V., Staurengo-Ferrari, L., Zaninelli, T.H. et al. IL-33 enhances macrophage release of IL-1β and promotes pain and inflammation in gouty arthritis. Inflamm. Res. 69, 1271–1282 (2020). https://doi.org/10.1007/s00011-020-01399-x

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