Renal Department, University Medical Center, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
EMBO J. 2018 Aug 1;37(15). doi: 10.15252/embj.201798615. Epub 2018 Jun 19.
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy-related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell-autonomous manner and results in peritubular accumulation of CCR2 mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis.
多囊肾病 (PKD) 和其他肾脏纤毛病的特征是囊肿、炎症和纤维化。纤毛作为信号中心发挥作用，但肾脏炎症与纤毛的分子联系尚未建立。在这里，我们表明肾脏上皮细胞中的纤毛激活趋化因子信号以招募炎症细胞。我们鉴定了一个包含纤毛激酶 LKB1 和几种纤毛病相关蛋白的复合物，包括 NPHP1 和 PKD1。在稳态下，这个纤毛模块抑制管状上皮细胞中趋化因子 CCL2 的表达。在小鼠肾小管中敲除 LKB1 或 PKD1 会以细胞自主的方式上调 CCL2 的表达，并导致 CCR2 单核吞噬细胞在肾小管周围积聚，促进纤毛病表型。我们的发现确立了上皮细胞器纤毛作为组织免疫细胞数量的守门员。这代表了肾脏纤毛病的一种意外疾病机制，并为上皮细胞如何调节免疫细胞影响组织稳态建立了一个新模型。
