Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity.

Elena Montes-Cobos,Fred Lühder,Henrike J Fischer,Holger M Reichardt,Nils Schweingruber,Xiao Li

doi:10.3389/fimmu.2017.01319

Abstract

Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polarized cells contribute to tissue repair and anti-inflammatory processes. Here, we show that deletion of the mineralocorticoid receptor (MR) in bone marrow-derived macrophages and peritoneal macrophages caused their polarization toward the M2 phenotype with its distinct gene expression, altered phagocytic and migratory properties, and dampened NO production. After induction of EAE, mice that are selectively devoid of the MR in their myeloid cells (MRlysM mice) showed diminished clinical symptoms and ameliorated histological hallmarks of neuroinflammation. T cells in peripheral lymphoid organs of these mice produced less pro-inflammatory cytokines while their proliferation and the abundance of regulatory T cells were unaltered. The numbers of inflammatory monocytes and reactive microglia in the central nervous system (CNS) in MRlysM mice were significantly lower and they adopted an M2-polarized phenotype based on their gene expression profile, presumably explaining the ameliorated neuroinflammation. Our results indicate that the MR in myeloid cells plays a critical role for CNS autoimmunity, providing a rational to interfere with diseases such as MS by pharmacologically targeting this receptor.

Highlights

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with significant socio-economic relevance, most often affecting young adults
We found that mice with a myeloid cell-specific mineralocorticoid receptor (MR) deficiency were partially protected from EAE due to an altered polarization of macrophages, monocytes, and microglia as well as indirect effects on T cells, supporting an important role of myeloid cells as target for GC in MS
It has been noted that activation of the MR by specific agonists including GC induces a pro-inflammatory phenotype in myeloid cells [9, 35], and it has been shown that Peritoneal macrophages (PM) lacking the MR have a different transcriptional profile resembling M2-polarized macrophages [9, 23, 36]

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with significant socio-economic relevance, most often affecting young adults. New therapeutic approaches with activity in MS patients have been developed, such as monoclonal antibodies targeting CD20, CD25, CD52, or MR in Neuroinflammatory Disease α4 integrin, and small molecule compounds such as fingolimod, demethyl fumarate, and laquinimod [3] While these new therapeutics have considerably improved the management of MS, they bring with them adverse effects that at least partially constrain their use. Application of the anti-CD52 antibody Alemtuzumab can cause autoimmune diseases such as Hashimoto thyroiditis, whereas therapy with the anti-α4 integrin antibody Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy. It is against this background that research aimed at identifying drug targets suitable for MS therapy is still warranted. It is a member of the nuclear receptor superfamily, plays a significant role in the regulation of the immune system, and can be targeted by clinically approved compounds that have been in use for many years [5]

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