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

• Amandine Viau ^[2] ; Frank Bienaimé ^[3] ; Kamile Lukas ^[4] ; Abhijeet P Todkar ^[4] ; Manuel Knoll ^[5] ; Toma A Yakulov ^[6] ; Alexis Hofherr ^[6] ; Oliver Kretz ^[7] ; Martin Helmstädter ^[6] ; Wilfried Reichardt ^[1] ; Simone Braeg ^[4] ; Tom Aschman ^[5] ; Annette Merkle ^[8] ; Dietmar Pfeifer ^[1] ; Verónica I Dumit ^[9] ; Marie‐Claire Gubler ^[10] ; Roland Nitschke ^[11] ; Tobias B Huber ^[12] ; Fabiola Terzi ^[13] ; Jörn Dengjel ^[14] ; Florian Grahammer ^[15] ; Michael Köttgen ^[6] ; Hauke Busch ^[16] ; Melanie Boerries ^[17] ; Gerd Walz ^[18] ; Antigoni Triantafyllopoulou ^[1] ; E Wolfgang Kuehn ^[18]
  1. [1] University of Freiburg

     University of Freiburg

     Stadtkreis Freiburg im Breisgau, Alemania

     
  2. [2] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 3 INSERM U1151 Institut Necker Enfants Malades Department of Growth and Signaling Université Paris Descartes‐Sorbonne Paris Cité Paris France
  3. [3] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 3 INSERM U1151 Institut Necker Enfants Malades Department of Growth and Signaling Université Paris Descartes‐Sorbonne Paris Cité Paris France; 4 Service d'Explorations Fonctionnelles Hôpital Necker‐Enfants Malades Paris France
  4. [4] 1 Renal Department University Medical Center Freiburg Germany
  5. [5] 5 Department of Rheumatology and Clinical Immunology University Medical Center Freiburg Germany
  6. [6] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany
  7. [7] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 6 Department of Neuroanatomy Albert‐Ludwigs‐University Freiburg Freiburg Germany; 7 III. Department of Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany
  8. [8] 8 Medical Physics, Department of Radiology, and Comprehensive Cancer Center University Medical Center Freiburg Germany
  9. [9] 12 Center for Biological Systems Analysis (ZBSA) Core Facility Proteomics Albert‐Ludwigs‐University Freiburg Freiburg Germany
  10. [10] 13 INSERM UMR1163 Laboratory of Inherited Kidney Diseases Necker‐Enfants Malades Hospital Paris France; 14 Imagine Institute Université Paris Descartes‐Sorbonne Paris Cité Paris France
  11. [11] 15 Center for Biological Systems Analysis (ZBSA) Life Imaging Center Albert‐Ludwigs‐University Freiburg Freiburg Germany; 16 Center for Biological Signaling Studies (BIOSS) Albert‐Ludwigs‐University Freiburg Freiburg Germany
  12. [12] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 7 III. Department of Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany; 16 Center for Biological Signaling Studies (BIOSS) Albert‐Ludwigs‐University Freiburg Freiburg Germany; 17 Center for Biological Systems Analysis (ZBSA) Albert‐Ludwigs‐University Freiburg Freiburg Germany
  13. [13] 3 INSERM U1151 Institut Necker Enfants Malades Department of Growth and Signaling Université Paris Descartes‐Sorbonne Paris Cité Paris France
  14. [14] 12 Center for Biological Systems Analysis (ZBSA) Core Facility Proteomics Albert‐Ludwigs‐University Freiburg Freiburg Germany; 18 Department of Biology University of Fribourg Fribourg Switzerland
  15. [15] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 7 III. Department of Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany
  16. [16] 9 German Cancer Consortium (DKTK) Freiburg Germany; 10 German Cancer Research Center (DKFZ) Heidelberg Germany; 19 Institute of Experimental Dermatology University of Lübeck Lübeck Germany
  17. [17] 9 German Cancer Consortium (DKTK) Freiburg Germany; 10 German Cancer Research Center (DKFZ) Heidelberg Germany; 20 Systems Biology of the Cellular Microenvironment Group Institute of Molecular Medicine and Cell Research (IMMZ) Albert‐Ludwigs‐University Freiburg Germany
  18. [18] 1 Renal Department University Medical Center Freiburg Germany; 2 Faculty of Medicine University of Freiburg Freiburg Germany; 16 Center for Biological Signaling Studies (BIOSS) Albert‐Ludwigs‐University Freiburg Freiburg Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 15, 2018
• Idioma: inglés
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  • 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.