Project Details
Projekt
The mineralocorticoidreceptor in myeloid cells - a new player in CNS autoimmunity
Subject Area
Immunology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 273444380
Our previous work focused on the role of the glucocorticoid receptor (GR) in T cells for the pathogenesis of EAE and multiple sclerosis (MS). However, there is another receptor capable of binding glucocorticoids (GCs) besides the GR, namely the mineralocorticoid receptor (MR), which is expressed in myeloid cells and could therefore mediate relevant effects of GCs in the modulation of neuroinflammatory diseases. Therefore we performed several pilot experiments which suggested that disruption of the MR in myeloid cells has a significant impact on EAE as well. Hence, the purpose of the follow-up project is to explore the role of the MR in the control of neuroinflammation by GCs in more detail and to identify the mechanisms involved. In the first part of the project we want to study EAE in myeloid cell-specific MR knock-out mice (MRlysM). This includes a detailed phenotypic and functional characterization of different types of myeloid cells during the course of EAE, both in peripheral lymphoid organs and the CNS. These studies will be complemented by immunohistochemical analyses of the spinal cord. Since the MR is expressed in distinct subtypes of myeloid cells we will investigate whether their composition is altered and to which extent the microglia contributes to the observed phenotype. In addition, we want to study pathogenic T cells which might be indirectly affected by the absence of the MR in myeloid cells. In the second part we plan to analyze migration of myeloid cells. Because CNS infiltration of macrophages is diminished in MRlysM mice we will perform in vitro transmigration assays of myeloid cells obtained from naïve and EAE mice. Subsequently, we will use 2-photon microscopy to test in vivo whether and how MR-deficiency may affect monocyte migration in response to different stimuli. In the third part we will built upon our finding that application of the MR antagonist Aldactone® ameliorates EAE. Initially, we will compare two different application protocols and then try to understand the mechanism underlying pharmacological MR blockade. Collectively, we expect that our studies will clarify the role of the MR in myeloid cells for the pathogenesis and therapy of neuroinflammatory diseases and allow a first assessment of whether MR antagonists might be suitable for the treatment of CNS inflammation in patients. Since such inhibitors are already in clinical use, our results might pave the way for translational studies in the future.
DFG Programme
Research Grants
