Myeloid cell-specific ablation of the mineralocorticoid receptor attenuates experimental autoimmune encephalomyelitis

Myeloid cell-specific ablation of the mineralocorticoid receptor attenuates experimental autoimmune encephalomyelitis

Xiao Li

Doctoral thesis

Date of Examination: 2013-01-14

Date of issue: 2013-02-12

Advisor: Reichardt, Holger Prof. Dr.

Referee: Walter, Lutz Prof. Dr.

Referee: Johnsen, Steven A. Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-000D-FB53-E

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Abstract

English

The mineralocorticoid receptor (MR) plays an essential role in regulating fluid and electrolyte homeostasis. Amongst hematopoietic cells, also macrophages express the MR but, unlike kidney or colon, they do not co-express the enzyme 11β-hydroxysteroid dehydrogenase type II (11β-HSDII). Consequently, glucocorticoids (GC) in macrophages are able not only to activate the GC receptor (GR) but also the MR, and the balance between both effects determines macrophage fate. It had been hypothesized that the absence of the MR induces polarization towards alternatively activated macrophages (AAM), which are known to have anti-inflammatory and wound-healing features. The aim of this study was to obtain further insight into the role of the MR in macrophage polarization and its effects on neuroinflammation in vivo. This work shows that MR knockout macrophages are skewed towards an AAM phenotype. However, these AAMs have different characteristics compared to those induced by IL-4 and IL-13. In vitro, MR knockout macrophages are characterized by reduced iNOS and increase in Arginase1 expression. This is supported by in vivo results obtained by inducing experimental autoimmune encephalomyelitis (EAE) mimicking multiple sclerosis (MS) in MRlysMcre and MRflox/flox mice. In this disease model, the mutant mice suffer significantly less from EAE than control mice. Macrophages both from the spinal cord and the peritoneal cavity of diseased MRlysMcre mice show a polarization towards the AAM phenotype. Histological analysis of MRlysMcre mice suffering from EAE confirmed that the pathophysiological features were less severe compared to control mice. Thus, ablation of the MR in macrophages induces their polarization towards AAM thereby ameliorating EAE. Since MR disruption from early development on may induce compensatory mechanisms, new transgenic mice should be developed allowing for an inducible and reversible deletion of the MR in the hematopoietic system. To this end lentiviral vectors for the inactivation of the MR by RNA interference were successfully developed and tested. They were produced at high titers, injected into fertilized mouse oocytes and transgenic offspring was identified that had integrated the new vector. In the future, this new model should become instrumental in analyzing the role of the MR in the control of the immune system.

Keywords: Mineralocorticoid receptor; macrophage polarization; EAE