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Requirement of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Protease Activity for Fcγ Receptor–Induced Arthritis, but Not Fcγ Receptor–Mediated Platelet Elimination, in Mice
Author(s) -
Martin Kea,
Touil Ratiba,
Cvijetic Grozdan,
Israel Laura,
Kolb Yeter,
Sarret Sophie,
Valeaux Stéphanie,
Degl'Innocenti Elena,
Le Meur Thomas,
Caesar Nadja,
Bardet Maureen,
Beerli Christian,
Zerwes HansGuenter,
Kovarik Jiri,
Beltz Karen,
Schlapbach Achim,
Quancard Jean,
Régnier Catherine H.,
Bigaud Marc,
Junt Tobias,
Wieczorek Grazyna,
Isnardi Isabelle,
LittlewoodEvans Amanda,
Bornancin Frédéric,
Calzascia Thomas
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41204
Subject(s) - proinflammatory cytokine , immunology , immune system , biology , arthritis , cancer research , chemistry , inflammation
Objective Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain–containing protein 9, B cell CLL/lymphoma 10, and mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT‐1) is required for optimal FcγR‐induced canonical NF‐κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT ‐1 protease activity in FcγR‐driven events and evaluate the therapeutic potential of selective MALT ‐1 protease inhibitors in FcγR‐mediated diseases. Methods Using genetic and pharmacologic disruption of MALT ‐1 scaffolding and enzymatic activity, we assessed the relevance of MALT ‐1 function in murine and human primary myeloid cells upon stimulation with immune complexes ( IC s) and in murine models of autoantibody‐driven arthritis and immune thrombocytopenic purpura ( ITP ). Results MALT ‐1 protease function is essential for optimal FcγR‐induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with IC s. In contrast, MALT ‐1 protease inhibition did not affect the Syk‐dependent, FcγR‐mediated production of reactive oxygen species or leukotriene B 4 . Notably, pharmacologic MALT ‐1 protease inhibition in vivo reduced joint inflammation in the murine K/BxN serum–induced arthritis model (mean area under the curve for paw swelling of 45.42% versus 100% in control mice; P = 0.0007) but did not affect platelet depletion in a passive model of ITP . Conclusion Our findings indicate a specific contribution of MALT ‐1 protease activity to FcγR‐mediated events and suggest that MALT ‐1 protease inhibitors have therapeutic potential in a subset of FcγR‐driven inflammatory disorders.