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
  • Chemokine CCL2/metabolism*
  • Carrier Proteins/metabolism
  • Cell Line
  • Dogs
  • HEK293 Cells
  • Zebrafish
  • Protein Serine-Threonine Kinases/genetics*
  • Protein Serine-Threonine Kinases/metabolism
  • Female
  • Macrophages/metabolism
  • Kidney Tubules/cytology
  • Kidney Tubules/pathology
  • Madin Darby Canine Kidney Cells
  • Kidney Diseases, Cystic/congenital*
  • Kidney Diseases, Cystic/pathology
  • Epithelial Cells/metabolism
  • Animals
  • Mice, Knockout
  • Mice
  • Phagocytosis/physiology
  • Humans
  • Mice, Inbred C57BL
  • Polycystic Kidney, Autosomal Dominant/genetics
  • Polycystic Kidney, Autosomal Dominant/pathology*
  • Male
  • Protein Kinase C/genetics*
  • Protein Kinase C/metabolism
  • Cilia/pathology*
(all 28)
PubMed
29925518 Full text @ EMBO J.
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
Figures
Figure Gallery (1 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
li1Tg + MO1-nphp1 + MO3-stk11 + MO4-tp53standard conditionsLong-pec
li1Tg + MO1-nphp1 + MO4-tp53standard conditionsLong-pec
li1Tg + MO3-stk11 + MO4-tp53standard conditionsLong-pec
1 - 3 of 3
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
li1TgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    ciliopathyTAS
    polycystic kidney diseaseTAS
    1 - 2 of 2
    Show
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    nphp1MO1-nphp1MRPHLNO
    stk11MO3-stk11MRPHLNO
    tp53MO4-tp53MRPHLNO
    1 - 3 of 3
    Show
    Fish
    Fish
    li1Tg + MO1-nphp1 + MO3-stk11 + MO4-tp53
    li1Tg + MO1-nphp1 + MO4-tp53
    li1Tg + MO3-stk11 + MO4-tp53
    1 - 3 of 3
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available
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    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).