Cilia‐localized LKB1 regulates chemokine signaling,macrophage recruitment,and tissue homeostasis in the kidney |
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| Authors: | 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 Dengjel Florian Grahammer Michael Köttgen Hauke Busch Melanie Boerries Gerd Walz Antigoni Triantafyllopoulou E Wolfgang Kuehn |
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| Affiliation: | 1. Renal Department, University Medical Center, Freiburg, Germany;2. Department of Rheumatology and Clinical Immunology, University Medical Center, Freiburg, Germany;3. Faculty of Medicine, University of Freiburg, Freiburg, Germany;4. Department of Neuroanatomy, Albert‐Ludwigs‐University Freiburg, Freiburg, Germany;5. III. Department of Medicine, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;6. Medical Physics, Department of Radiology, and Comprehensive Cancer Center, University Medical Center, Freiburg, Germany;7. German Cancer Consortium (DKTK), Freiburg, Germany;8. German Cancer Research Center (DKFZ), Heidelberg, Germany;9. Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany;10. Center for Biological Systems Analysis (ZBSA), Core Facility Proteomics, Albert‐Ludwigs‐University Freiburg, Freiburg, Germany;11. INSERM UMR1163, Laboratory of Inherited Kidney Diseases, Necker‐Enfants Malades Hospital, Paris, France;12. Imagine Institute, Université Paris Descartes‐Sorbonne Paris Cité, Paris, France;13. Center for Biological Systems Analysis (ZBSA), Life Imaging Center, Albert‐Ludwigs‐University Freiburg, Freiburg, Germany;14. Center for Biological Signaling Studies (BIOSS), Albert‐Ludwigs‐University Freiburg, Freiburg, Germany;15. Center for Biological Systems Analysis (ZBSA), Albert‐Ludwigs‐University Freiburg, Freiburg, Germany;16. INSERM U1151, Institut Necker Enfants Malades, Department of Growth and Signaling, Université Paris Descartes‐Sorbonne Paris Cité, Paris, France;17. Department of Biology, University of Fribourg, Fribourg, Switzerland;18. Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany;19. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research (IMMZ), Albert‐Ludwigs‐University, Freiburg, Germany;20. Department of Rheumatology and Clinical Immunology, Charité ‐ University Medical Centre Berlin, Berlin, Germany |
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| 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. |
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| Keywords: | cilia macrophages nephronophthisis polycystic kidney disease |
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