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

Media type: E-Article
Title: 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
Contributor: 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, Hans‐Guenter; Kovarik, Jiri; Beltz, Karen; Schlapbach, Achim; Quancard, Jean; Régnier, Catherine H.; Bigaud, Marc; Junt, Tobias; Wieczorek, Grazyna; Isnardi, Isabelle; Littlewood‐Evans, Amanda; Bornancin, Frédéric;
imprint: Wiley, 2020
Published in: Arthritis & Rheumatology
Language: English
DOI: 10.1002/art.41204
ISSN: 2326-5191; 2326-5205
Keywords: Immunology ; Rheumatology ; Immunology and Allergy
Origination:
Footnote:
Description: <jats:sec><jats:title>Objective</jats:title><jats:p>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 <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease activity in FcγR‐driven events and evaluate the therapeutic potential of selective <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease inhibitors in FcγR‐mediated diseases.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Using genetic and pharmacologic disruption of <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 scaffolding and enzymatic activity, we assessed the relevance of <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 function in murine and human primary myeloid cells upon stimulation with immune complexes (<jats:styled-content style="fixed-case">IC</jats:styled-content>s) and in murine models of autoantibody‐driven arthritis and immune thrombocytopenic purpura (<jats:styled-content style="fixed-case">ITP</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease function is essential for optimal FcγR‐induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with <jats:styled-content style="fixed-case">IC</jats:styled-content>s. In contrast, <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease inhibition did not affect the Syk‐dependent, FcγR‐mediated production of reactive oxygen species or leukotriene B<jats:sub>4</jats:sub>. Notably, pharmacologic <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐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; <jats:italic>P</jats:italic> = 0.0007) but did not affect platelet depletion in a passive model of <jats:styled-content style="fixed-case">ITP</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings indicate a specific contribution of <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease activity to FcγR‐mediated events and suggest that <jats:styled-content style="fixed-case">MALT</jats:styled-content>‐1 protease inhibitors have therapeutic potential in a subset of FcγR‐driven inflammatory disorders.</jats:p></jats:sec>
Access State: Open Access

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