Control of homeostasis of dendritic cells by the GTPase RhoA [thesis]

Shuai Li
2016
Lymphoid and non-lymphoid tissues accommodate defined numbers of dendritic cells (DCs). There, DC-life span is influenced by various components such as proliferation and cell division triggered by cytokines, maturation processes in response to extracellular inflammatory and microbial substances, as well as induction of migration and apoptosis. Previous work has demonstrated the importance of specific numbers of DCs in tissues, as changes of DC numbers or DC life span could alter immunity,
more » ... nce or inflammation resulting in various immune diseases. However, currently it is still unknown how DC life span and homeostasis is regulated in vivo. RhoA is a member of Rho GTPase-family, which plays important roles in regulating cytoskeleton organization, proliferation, migration and survival. However, our current knowledge about RhoA-functions is based mostly on studies using dominant negative and constitutively active RhoA-mutants, which have possible unspecific effects on other members of the Rho GTPase family. Therefore, we used a LoxP/Cre recombinase approach to knock out RhoA selectively in DCs. Here we found that GTPase RhoA controlled the homeostasis of mature DCs, and deletion of RhoA caused significantly reduced numbers of CD8+CD11b- and CD11b+Esamhi DC subsets, while CD11b+Esamlo DCs remained largely unaltered. Loss of RhoA interfered with homeostatic proliferation, cytokinesis, survival and turnover of cDCs. By performing proteomic analysis, we found that a pro-survival PI3Kγ/Akt/BAD pathway was deregulated in RhoA-ko DCs. Taken together, our findings indicate that RhoA plays a critical role in regulating DC-homeostasis, deletion of which decreases DC numbers resulting in impaired immune protection.
doi:10.5282/edoc.19264 fatcat:d3qnzkmokfhijgu7dlviud3dtq