The Parkinson's disease-associated gene, LRRK2, is also associated with immune disorders and infectious disease and is expressed in immune subsets. Here, we characterize a platform for interrogating the expression and function of endogenous LRRK2 in authentic human phagocytes using human induced pluripotent stem cell-derived macrophages and microglia. Endogenous LRRK2 is expressed and upregulated by interferon-γ in these cells, including a 187-kDa cleavage product. Using LRRK2 knockout and G2019S isogenic repair lines, we find that LRRK2 is not involved in initial phagocytic uptake of bioparticles but is recruited to LAMP1⁺/RAB9⁺ “maturing” phagosomes, and LRRK2 kinase inhibition enhances its residency at the phagosome. Importantly, LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes, implying that LRRK2 operates at the intersection between phagosome maturation and recycling pathways in these professional phagocytes.

帕金森氏病相关基因LRRK2也与免疫疾病和传染病有关，并以免疫亚群表达。在这里，我们表征了一个平台，用于使用人类诱导的多能干细胞衍生的巨噬细胞和小胶质细胞，在真实的人类吞噬细胞中询问内源性LRRK2的表达和功能。内源性LRRK2在这些细胞中被干扰素-γ表达和上调，包括187 kDa的裂解产物。使用LRRK2基因敲除和G2019S等基因修复线，我们发现，LRRK2不参与生物粒子的初始巨噬细胞吞噬，但被招募到LAMP1 ⁺ /内Rab9 ⁺“成熟”的吞噬体，LRRK2激酶抑制作用增强了其在吞噬体中的驻留能力。重要的是，RAB8a和RAB10募集到吞噬体需要LRRK2，这意味着LRRK2在这些专业吞噬细胞的吞噬体成熟和循环途径之间的交叉点起作用。