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 (ICs) 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 ICs. In contrast, MALT-1 protease inhibition did not affect the Syk-dependent, FcγR-mediated production of reactive oxygen species or leukotriene B4 . 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.

中文翻译：

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黏膜相关淋巴组织淋巴瘤易位蛋白1蛋白酶活性对Fcγ受体诱导的关节炎的作用，但对Fcγ受体介导的血小板清除作用没有影响。

目的Fcγ受体（FcγR）在保护性和致病性免疫反应中均起重要作用。包含胱天蛋白酶募集结构域蛋白9，B细胞CLL /淋巴瘤10和黏膜相关淋巴样组织淋巴瘤易位蛋白1（MALT-1）的CBM信号体的组装是最佳FcγR诱导的典型NF-κB激活和促炎细胞因子释放。进行这项研究以阐明MALT-1蛋白酶活性与FcγR驱动的事件的相关性，并评估选择性MALT-1蛋白酶抑制剂在FcγR介导的疾病中的治疗潜力。方法利用MALT-1支架的遗传和药理学破坏以及酶活性，我们评估了免疫复合物（ICs）和自身抗体驱动的关节炎和免疫性血小板减少性紫癜（ITP）的小鼠模型刺激后，鼠类和人类原代骨髓细胞中MALT-1功能的相关性。结果MALT-1蛋白酶功能对于由Fc刺激IC刺激的各种鼠类和人骨髓细胞最佳FcγR诱导的促炎细胞因子产生至关重要。相反，MALT-1蛋白酶抑制作用不影响Syk依赖性，FcγR介导的活性氧或白三烯B4的产生。值得注意的是，在小鼠K / BxN血清诱导的关节炎模型中，药理学MALT-1蛋白酶的体内抑制作用减轻了关节炎症（爪肿胀曲线下的平均面积为45.42％，对照组为100％； P = 0.0007），但没有在ITP的被动模型中影响血小板耗竭。