Control of Homeostasis and Dendritic Cell Survival by the GTPase RhoA

Shuai Li; Bastian Dislich; Cord H Brakebusch; Stefan F Lichtenthaler; Thomas Brocker

doi:10.4049/jimmunol.1500676

Control of Homeostasis and Dendritic Cell Survival by the GTPase RhoA

J Immunol. 2015 Nov 1;195(9):4244-56. doi: 10.4049/jimmunol.1500676. Epub 2015 Sep 25.

Authors

Shuai Li¹, Bastian Dislich², Cord H Brakebusch³, Stefan F Lichtenthaler⁴, Thomas Brocker⁵

Affiliations

¹ Institute for Immunology, Ludwig-Maximilians-University, 80336 Munich, Germany;
² German Center for Neurodegenerative Diseases, 81377 Munich, Germany;
³ Biotech Research and Innovation Center, Molecular Pathology Section, 2200 Copenhagen, Denmark;
⁴ German Center for Neurodegenerative Diseases, 81377 Munich, Germany; Neuroproteomics, Technical University Munich, 81675 Munich, Germany; and Munich Cluster for Systems Neurology, 81377 Munich, Germany.
⁵ Institute for Immunology, Ludwig-Maximilians-University, 80336 Munich, Germany; [email protected].

PMID: 26408665
DOI: 10.4049/jimmunol.1500676

Abstract

Tissues accommodate defined numbers of dendritic cells (DCs) in highly specific niches where different intrinsic and environmental stimuli control DC life span and numbers. DC homeostasis in tissues is important, because experimental changes in DC numbers influence immunity and tolerance toward various immune catastrophes and inflammation. However, the precise molecular mechanisms regulating DC life span and homeostasis are unclear. We report that the GTPase RhoA controls homeostatic proliferation, cytokinesis, survival, and turnover of cDCs. Deletion of RhoA strongly decreased the numbers of CD11b(-)CD8(+) and CD11b(+)Esam(hi) DC subsets, whereas CD11b(+)Esam(lo) DCs were not affected in conditional RhoA-deficient mice. Proteome analyses revealed a defective prosurvival pathway via PI3K/protein kinase B (Akt1)/Bcl-2-associated death promoter in the absence of RhoA. Taken together, our findings identify RhoA as a central regulator of DC homeostasis, and its deletion decreases DC numbers below critical thresholds for immune protection and homeostasis, causing aberrant compensatory DC proliferation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Apoptosis / immunology*
Blotting, Western
Bone Marrow Cells / immunology
Bone Marrow Cells / metabolism
CD11c Antigen / immunology
CD11c Antigen / metabolism
Cell Proliferation / genetics
Cell Survival / genetics
Cell Survival / immunology
Cells, Cultured
Cytokinesis / genetics
Cytokinesis / immunology
Dendritic Cells / immunology*
Dendritic Cells / metabolism
Flow Cytometry
Homeostasis / genetics
Homeostasis / immunology*
Membrane Proteins / immunology
Membrane Proteins / metabolism
Mice, Knockout
Mice, Transgenic
Phosphatidylinositol 3-Kinases / immunology
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / immunology
Proto-Oncogene Proteins c-akt / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Signal Transduction / immunology
Spleen / cytology
Spleen / immunology
Spleen / metabolism
bcl-Associated Death Protein / immunology
bcl-Associated Death Protein / metabolism
rhoA GTP-Binding Protein / genetics
rhoA GTP-Binding Protein / immunology*
rhoA GTP-Binding Protein / metabolism

Substances

CD11c Antigen
Membrane Proteins
bcl-Associated Death Protein
flt3 ligand protein
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
rhoA GTP-Binding Protein