Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

Amandine Viau, Frank Bienaimé, Kamile Lukas, Abhijeet P Todkar, Manuel Knoll, Toma A Yakulov, Alexis Hofherr, Oliver Kretz, Martin Helmstädter, Wilfried Reichardt, Simone Braeg, Tom Aschman, Annette Merkle, Dietmar Pfeifer, Verónica I Dumit, Marie-Claire Gubler, Roland Nitschke, Tobias B Huber, Fabiola Terzi, Jörn DengjelFlorian Grahammer, Michael Köttgen, Hauke Busch, Melanie Boerries, Gerd Walz, Antigoni Triantafyllopoulou, E Wolfgang Kuehn

Abstract

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.

OriginalspracheEnglisch
ZeitschriftThe EMBO journal
Jahrgang37
Ausgabenummer15
ISSN0261-4189
DOIs
PublikationsstatusVeröffentlicht - 01.08.2018

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