The Leucine Rich Repeat Kinase 2 (LRRK2) is one of causative genes of familial Parkinson’s disease (PD). The M2397T polymorphism in LRRK2 is genetically associated with sporadic Crohn’s disease (CD). LRRK2 is expressed in human CD14⁺ monocytes, induced by interferon-γ (IFN-γ) and suppresses inflammatory activation. We hypothesize that IFN-γ-induced LRRK2 and inflammatory gene expression is altered by LRRK2 genetic polymorphism found in CD and PD cases. A total of 46 CD and 51 control cases, and 16 PD cases and 16 PD-linked LRRK2 mutation cases were recruited. Live human CD14⁺ monocytes were isolated from donors for ex vivo IFN-γ stimulation and gene expression analysis. IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A). The 2397-M/M CD risk allele enhanced IFN-γ responses of CD14⁺ cells in CD but not in control group. CD14⁺ monocytes from G2019S and R1441C LRRK2 mutated PD cases and carriers show no changes in IFN-γ responses for TNFA or IL12, reduced response for HLADRA1, and enhanced responses for LRRK2 in FK506-sensitive manner. These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14⁺ monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response.

Graphical Abstract

富含亮氨酸的重复激酶 2 ( LRRK2 ) 是家族性帕金森病 (PD) 的致病基因之一。LRRK2中的 M2397T 多态性在遗传上与散发性克罗恩病 (CD) 相关。LRRK2 在人 CD14 ⁺单核细胞中表达，由干扰素-γ (IFN-γ) 诱导并抑制炎症激活。我们假设在 CD 和 PD 病例中发现的LRRK2基因多态性改变了 IFN-γ 诱导的 LRRK2 和炎症基因表达。共招募了 46 例 CD 和 51 例对照病例，以及 16 例 PD 病例和 16 例 PD 相关的LRRK2突变病例。活人 CD14 ⁺从供体中分离单核细胞用于离体 IFN-γ 刺激和基因表达分析。IFN-γ 有效增强TNFA、IL12、HLADRA1 和 LRRK2的表达，这被 FK506（一种钙调神经磷酸酶特异性抑制剂）抑制，但被 LRRK2 特异性激酶抑制剂 (GSK2578215A) 进一步增强。2397-M/M CD 风险等位基因增强了 CD 中 CD14 ⁺细胞的 IFN-γ 反应，但在对照组中没有。来自 G2019S 和 R1441C LRRK2突变的 PD 病例和携带者的CD14 ^{+单核细胞对}TNFA或IL12的 IFN-γ 反应没有变化，对HLADRA1 的反应降低，对LRRK2的反应增强以 FK506 敏感的方式。这些数据表明，CD 相关的LRRK2突变是 CD14 ⁺单核细胞先天免疫反应的重要调节剂，而 PD 相关的LRRK2突变可能有助于降低抗原呈递反应。

图形概要