PUBLICATION
Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney
- Authors
- Viau, A., Bienaimé, F., Lukas, K., Todkar, A.P., Knoll, M., Yakulov, T.A., Hofherr, A., Kretz, O., Helmstädter, M., Reichardt, W., Braeg, S., Aschman, T., Merkle, A., Pfeifer, D., Dumit, V.I., Gubler, M.C., Nitschke, R., Huber, T.B., Terzi, F., Dengjel, J., Grahammer, F., Köttgen, M., Busch, H., Boerries, M., Walz, G., Triantafyllopoulou, A., Kuehn, E.W.
- ID
- ZDB-PUB-190418-20
- Date
- 2018
- Source
- The EMBO journal 37(15): (Journal)
- Registered Authors
- Keywords
- cilia, macrophages, nephronophthisis, polycystic kidney disease
- MeSH Terms
-
- Kidney Tubules/cytology
- Kidney Tubules/pathology
- Zebrafish
- Mice, Knockout
- Mice
- HEK293 Cells
- Epithelial Cells/metabolism
- Humans
- Polycystic Kidney, Autosomal Dominant/genetics
- Polycystic Kidney, Autosomal Dominant/pathology*
- Male
- Female
- Macrophages/metabolism
- Chemokine CCL2/metabolism*
- Protein Serine-Threonine Kinases/genetics*
- Protein Serine-Threonine Kinases/metabolism
- Cell Line
- Cilia/pathology*
- Mice, Inbred C57BL
- Phagocytosis/physiology
- Animals
- Dogs
- Madin Darby Canine Kidney Cells
- Carrier Proteins/metabolism
- Protein Kinase C/genetics*
- Protein Kinase C/metabolism
- Kidney Diseases, Cystic/congenital*
- Kidney Diseases, Cystic/pathology
- PubMed
- 29925518 Full text @ EMBO J.
Citation
Viau, A., Bienaimé, F., Lukas, K., Todkar, A.P., Knoll, M., Yakulov, T.A., Hofherr, A., Kretz, O., Helmstädter, M., Reichardt, W., Braeg, S., Aschman, T., Merkle, A., Pfeifer, D., Dumit, V.I., Gubler, M.C., Nitschke, R., Huber, T.B., Terzi, F., Dengjel, J., Grahammer, F., Köttgen, M., Busch, H., Boerries, M., Walz, G., Triantafyllopoulou, A., Kuehn, E.W. (2018) Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. The EMBO journal. 37(15).
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping