An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis.
An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis.
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DOI：
10.1126/scitranslmed.aan8162
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发表时间：
2018-06-06
影响因子：
17.1
通讯作者：
Strober W
中科院分区：
文献类型：
--
作者：
Takagawa T;Kitani A;Fuss I;Levine B;Brant SR;Peter I;Tajima M;Nakamura S;Strober W
LRRK2/MUC19基因区域构成炎症性肠病（IBD）和帕金森病发生的高风险基因位点。我们发现，来自克罗恩病 (CD) 患者的树突状细胞 (DC) 和来自无 CD 但在该位点带有高风险等位基因 (rs11564258) 的杂合子的淋巴母细胞细胞系在体外表现出 LRRK2 表达增加。为了研究 LRRK2 表达增加的免疫学后果，我们在过度表达 Lrrk2 的转基因小鼠中进行了研究，结果表明这些小鼠表现出比同窝对照动物更严重的由葡聚糖硫酸钠 (DSS) 诱导的结肠炎。结肠炎严重程度的增加与固有层 DC 相关，固有层 DC 表现出 Dectin-1 诱导的 NF-κB 激活和促炎细胞因子分泌增加。结肠炎的严重程度是由 LRRK2 激活 NF-κB 通路成分（包括 TAK1 复合物和 TRAF6）驱动的。接下来，我们发现膜相关的 LRRK2（与 TAB2 相关）导致 Beclin-1 失活并抑制自噬。与野生型细胞相比，缺乏 Beclin-1 的 HCT116 结肠上皮细胞表现出 LRRK2 表达增加，表明抑制自噬可能会增强 LRRK2 促炎信号传导。然后我们发现，在对照和 Lrrk2 转基因动物中，LRRK2 抑制剂可减少小鼠 DC 中 Dectin-1 诱导的 TNF-α 产生，并改善 DSS 诱导的结肠炎。最后，我们证明 LRRK2 抑制剂可阻断 CD 患者培养的 DC 产生 TNF-α。我们的研究结果表明，LRRK2 激活正常化可能是治疗 IBD 的一种治疗方法，无论是否涉及 LRRK2 风险等位基因。
The LRRK2/MUC19 gene region constitutes a high-risk genetic locus for the occurrence of both inflammatory bowel diseases (IBDs) and Parkinson’s disease. We show that dendritic cells (DCs) from patients with Crohn’s disease (CD) and lymphoblastoid cell lines derived from patients without CD but bearing a high-risk allele (rs11564258) at this locus as heterozygotes exhibited increased LRRK2 expression in vitro. To investigate the immunological consequences of this increased LRRK2 expression, we conducted studies in transgenic mice over-expressing Lrrk2 and showed that these mice exhibited more severe colitis induced by dextran sodium sulfate (DSS) than did littermate control animals. This increase in colitis severity was associated with lamina propria DCs that showed increased Dectin-1–induced NF-κB activation and proinflammatory cytokine secretion. Colitis severity was driven by LRRK2 activation of NF-κB pathway components including the TAK1 complex and TRAF6. Next, we found that membrane-associated LRRK2 (in association with TAB2) caused inactivation of Beclin-1 and inhibition of autophagy. HCT116 colon epithelial cells lacking Beclin-1 exhibited increased LRRK2 expression compared to wild-type cells, suggesting that inhibition of autophagy potentially could augment LRRK2 proinflammatory signaling. We then showed that LRRK2 inhibitors decreased Dectin-1–induced TNF-α production by mouse DCs and ameliorated DSS-induced colitis, both in control and Lrrk2 transgenic animals. Finally, we demonstrated that LRRK2 inhibitors blocked TNF-α production by cultured DCs from patients with CD. Our findings suggest that normalization of LRRK2 activation could be a therapeutic approach for treating IBD, regardless of whether a LRRK2 risk allele is involved.
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