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Abstract
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by the infiltration of mononuclear cells into the CNS and a subsequent inflammation of the brain. Monocytes are implicated in disease pathogenesis not only in their function as potential antigen-presenting cells involved in the local reactivation of encephalitogenic T cells but also by independent effector functions contributing to structural damage and disease progression. However, monocytes also have beneficial effects as they can exert anti-inflammatory activity and promote tissue repair. Glucocorticoids (GCs) are widely used to treat acute relapses in MS patients. They act on a variety of cell types but their exact mechanisms of action including their modulation of monocyte function are not fully understood. Here we investigated effects of the therapeutically relevant GC methylprednisolone (MP) on monocytes from healthy individuals and MS patients in vitro and in vivo. The monocyte composition in the blood was different in MS patients compared to healthy individuals, but it was only marginally affected by MP treatment. In contrast, application of MP caused a marked shift toward an anti-inflammatory monocyte phenotype in vitro and in vivo as revealed by an altered gene expression profile. Chemotaxis of monocytes toward CCL2, CCL5, and CX3CL1 was increased in MS patients compared to healthy individuals and further enhanced by MP pulse therapy. Both of these migration-promoting effects were more pronounced in MS patients with an acute relapse than in those with a progressive disease. Interestingly, the pro-migratory GC effect was independent of chemokine receptor levels as exemplified by results obtained for CCR2. Collectively, our findings suggest that GCs polarize monocytes toward an anti-inflammatory phenotype and enhance their migration into the inflamed CNS, endowing them with the capacity to suppress the pathogenic immune response.
Highlights
Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving different types of immune cells including T cells, B cells, and monocytes
The Abundance of Classical CD14++CD16− Monocytes Is Increased in MS Patients Independently of Disease Activity
Monocytes were purified from the peripheral blood of healthy individuals and MS patients and analyzed for the distribution of cellular subsets by flow cytometry (Figure 1)
Summary
Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) involving different types of immune cells including T cells, B cells, and monocytes. Treatment of monocytes with GCs in vitro induces a stable anti-inflammatory gene expression profile [36] Such monocytes interfere with T-cell-mediated inflammation in vivo, where they were shown to directly suppress the secretion of IL-17 and IFNγ without inducing a direct Th2 shift. We found evidence that monocyte polarization becomes skewed toward the M2 phenotype by MP treatment and that the migration of monocytes along chemokine gradients is increased without any significant changes in the level of their respective receptors These findings suggest that GCs exert their beneficial effects on MS bouts by tuning monocyte function and not necessarily solely by suppressing T cells
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