Dysferlin deficiency enhances monocyte phagocytosis - A model for the inflammatory onset of limb-girdle muscular dystrophy 2B
Dysferlin deficiency enhances monocyte phagocytosis - A model for the inflammatory onset of limb-girdle muscular dystrophy 2B
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DOI：
10.2353/ajpath.2008.070327
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发表时间：
2008-03-01
影响因子：
6
通讯作者：
Hoffman, Eric P.
中科院分区：
文献类型：
--
作者：
Nagaraju, Kanneboyina;Rawat, Rashmi;Hoffman, Eric P.
Dysferlin缺乏导致肢带型肌营养不良2B型（LGMD 2B;近端无力）和Miyoshi肌病（远端无力）。肌肉炎症通常存在于dysferlin缺乏症中，并且患者经常被误诊为患有多发性肌炎。由于单核细胞通常表达dysferlin，我们假设dysferlin缺乏患者的单核细胞/巨噬细胞功能障碍可能有助于疾病的发作和进展。因此，我们研究了吞噬活性，在细胞因子的存在和不存在下，在新鲜分离的外周血单核细胞从LGMD 2B患者和SJL dysferlin缺陷的小鼠模型。与对照细胞相比，Dysferlin缺乏的单核细胞显示出增加的吞噬活性。在J774巨噬细胞系中，siRNA介导的dysferlin表达的抑制导致在基线和对肿瘤坏死因子-α的应答中的吞噬作用显著增强。免疫组织化学分析显示LGMD 2B人肌肉和SJL小鼠肌肉中几种单核细胞活化标志物的阳性染色。SJL肌肉表现出强烈的上调内吞蛋白CIMPR，网格蛋白，和adaptin-a，和LGMD 2B肌肉表现出衰变加速因子，这不是dysferlin特异性的表达减少。我们进一步表明，与对照细胞相比，在dysferlin缺陷的小鼠免疫细胞中，小Rho家族GTPases RhoA、Rac 1和Cdc 42的表达水平增加。因此，假设dysferlin缺乏肌肉中的轻度肌纤维损伤刺激炎症级联反应，可能引发、加剧并可能使潜在的肌纤维特异性营养不良过程永久化。
Dysferlin deficiency causes limb-girdle muscular dystrophy type 2B (LGMD2B; proximal weakness) and Miyoshi myopathy (distal weakness). Muscle inflammation is often present in dysferlin deficiency, and patients are frequently misdiagnosed as having polymyositis. Because monocytes normally express dysferlin, we hypothesized that monocyte/macrophage dysfunction in dysferlin-deficient patients might contribute to disease onset and progression. We therefore examined phagocytic activity, in the presence and absence of cytokines, in freshly isolated peripheral blood monocytes from LGMD2B patients and in the SJL dysferlin-deficient mouse model. Dysferlin-deflcient monocytes showed increased phagocytic activity compared with control cells. siRNA-mediated inhibition of dysferlin expression in the J774 macrophage cell line resulted in significantly enhanced phagocytosis, both at baseline and in response to tumor necrosis factor-a. Immunohistochemical analysis revealed positive staining for several mononuclear cell activation markers in LGMD2B human muscle and SJL mouse muscle. SJL muscle showed strong up-regulation of endocytic proteins CIMPR, clathrin, and adaptin-a, and LGMD2B muscle exhibited decreased expression of decay accelerating factor, which was not dysferlin-specific. We further showed that expression levels of small Rho family GTPases RhoA, Rac1, and Cdc 42 were increased in dysferlin-deficient murine immune cells compared with control cells. Therefore, hypothesize that mild myofiber damage in dysferlin-deficient muscle stimulates an inflammatory cascade that may initiate, exacerbate, and possibly perpetuate the underlying myofiber-specific dystrophic process.