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Inflammatory Potential of Four Different Phases of Calcium Pyrophosphate Relies on NF-kB Activation and MAPK Pathways

Campillo-Gimenez, Laure and Renaudin, Felix and Jalabert, Maud and Gras, Pierre and Gosset, Marjolaine and Rey, Christian and Sarda, Stéphanie and Collet, Corinne and Cohen-Solal, Martine and Combes, Christèle and Lioté, Frédéric and Ea, Hang-Korng Inflammatory Potential of Four Different Phases of Calcium Pyrophosphate Relies on NF-kB Activation and MAPK Pathways. (2018) Frontiers in Immunology. ISSN 1664-3224

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Official URL: https://doi.org/10.3389/fimmu.2018.02248


Background: Calcium pyrophosphate (CPP) microcrystal deposition is associated with wide clinical phenotypes, including acute and chronic arthritis, that are interleukin 1b (IL-1b)-driven. Two CPP microcrystals, namely monoclinic and triclinic CPP dihydrates (m- and t-CPPD), have been identified in human tissues in different proportions according to clinical features. m-CPP tetrahydrate beta (m-CPPTb) and amorphous CPP (a-CPP) phases are considered as m- and t-CPPD crystal precursors in vitro. Objectives: We aimed to decipher the inflammatory properties of the three crystalline phases and one amorphous CPP phase and the intracellular pathways involved. Methods: The four synthesized CPP phases and monosodium urate crystals (MSU, as a control) were used in vitro to stimulate the human monocytic leukemia THP-1 cell line or bone marrow-derived macrophages (BMDM) isolated from WT or NLRP3 KO mice. The gene expression of pro- and anti-inflammatory cytokines was evaluated by quantitative PCR; IL-1b, IL-6 and IL-8 production by ELISA; and mitogen-activated protein kinase (MAPK) activation by immunoblot analysis. NF-kB activation was determined in THP-1 cells containing a reporter plasmid. In vivo, the inflammatory potential of CPP phases was assessed with the murine air pouch model via cell analysis and production of IL-1b and CXCL1 in the exudate. The role of NF-kB was determined by a pharmacological approach, both in vivo and in vitro. Results: In vitro, IL-1b production induced by m- and t-CPPD and m-CPPTb crystals was NLRP3 inflammasome dependent. m-CPPD crystals were the most inflammatory by inducing a faster and higher production and gene expression of IL-1b, IL-6, and IL-8 than t-CPPD, m-CPPTb and MSU crystals. The a-CPP phase did not show an inflammatory property. Accordingly, m-CPPD crystals led to stronger activation of NF-kB, p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) MAPKs. Inhibition of NF-kB completely abrogated IL-1b and IL-8 synthesis and secretion induced by all CPP crystals. Also, inhibition of JNK and ERK1/2 MAPKs decreased both IL-1b secretion and NF-kB activation induced by CPP crystals. In vivo, IL-1b and CXCL1 production and neutrophil infiltration induced by m-CPPD crystals were greatly decreased by NF-kB inhibitor treatment. Conclusion: Our results suggest that the inflammatory potential of different CPP crystals relies on their ability to activate the MAPK-dependent NF-kB pathway. Studies are ongoing to investigate the underlying mechanisms.

Item Type:Article
HAL Id:hal-02178914
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Université de Toulouse > Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
French research institutions > Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE)
Other partners > Université de Paris Diderot - Paris 7 (FRANCE)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Other partners > Assistance publique - Hôpitaux de Paris - AP-HP (FRANCE)
Other partners > Université Paris Descartes - Paris V (FRANCE)
Laboratory name:
Agence Nationale de la Recherche
Deposited On:10 Jul 2019 09:35

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