LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson’s disease and Crohn’s disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson’s disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.

中文翻译：

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巨噬细胞 LRRK2 过度活跃损害自噬并诱导潘氏细胞功能障碍


LRRK2 多态性 （G2019S/N2081D） 增加对帕金森病和克罗恩病 （CD） 的易感性，导致 LRRK2 激酶过度活跃并抑制自噬。这种联系表明 LRRK2 激酶抑制（一种正在探索的帕金森病治疗策略）也可能使 CD 患者受益。潘氏细胞稳态受到自噬的严格调节，它们的功能障碍是 CD 中肠道炎症的前兆。在这里，我们发现 CD 患者和携带多动 LRRK2 多态性的小鼠发生了潘氏细胞功能障碍。我们还发现 LRRK2 激酶可以在基因（遗传自噬缺陷）和环境（吸烟）之间相互作用的背景下被激活。出乎意料的是，固有层免疫细胞是表达 LRRK2 的主要肠道细胞类型，而不是之前建议的潘氏细胞。我们发现 LRRK2 介导的吞噬细胞释放促炎细胞因子损害了潘氏细胞功能，LRRK2 激酶抑制通过激活自噬来挽救了潘氏细胞功能。总之，这些数据表明 LRRK2 激酶抑制剂通过恢复自噬来维持潘氏细胞稳态，可能代表了 CD 的一种治疗策略。