Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Cells. 2021 Feb 23;10(2):480. doi: 10.3390/cells10020480.
Mutations in gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn's disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.
基因突变导致常染色体显性遗传帕金森病（PD），并导致散发性 PD。LRRK2 中的常见遗传变异改变了对包括克罗恩病和麻风病在内的免疫性疾病的易感性。先前的研究报告称，LRRK2 在 B 淋巴细胞和巨噬细胞中表达，表明 LRRK2 在免疫功能中发挥作用。在这项研究中，我们使用人类淋巴母细胞来描述 LRRK2 蛋白的表达和磷酸化。脂多糖（LPS），一种促炎剂，以时间依赖性方式诱导人类淋巴母细胞中 LRRK2 表达和激酶活性的增加。此外，LPS 激活了 Toll 样受体（TLR）信号通路，增加了 TRAF6/LRRK2 的相互作用，并提高了 MAPK（JNK1/2、p38 和 ERK1/2）和 IkBα 的磷酸化水平。用 LRRK2 抑制剂 68 处理可减少 LPS 诱导的 TRAF6/LRRK2 相互作用以及 MAPK 和 IkBα 的磷酸化，从而减少 TNF-α 的分泌。这些结果表明，LRRK2 积极参与人类淋巴母细胞中的促炎反应，并且 68 通过抑制 GTP 结合可发挥针对促炎刺激的抗炎作用。这些发现不仅为 B 细胞样淋巴母细胞中 LRRK2 相关的免疫和炎症反应的机制提供了新的见解，而且还表明 68 可能对 LRRK2 相关的免疫性疾病也具有潜在的治疗价值。
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