Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes

Abstract

ObjectiveMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Myeloid phagocytes, including blood monocytes recruited to demyelinating lesions, may play a dual role in MS: on one hand, they might enhance CNS damage after differentiating toward a proinflammatory phenotype; on the other, they promote remyelination and repair through effective phagocytosis of myelin debris. We have previously determined that the retinoid X receptor (RXR) plays an important role in monocyte phagocytosis of myelin. Peroxisome proliferator‐activated receptor γ is an RXR binding partner that plays a key role in myeloid cell biology and is targeted by the thiazolidinedione group of antidiabetics such as pioglitazone. Consequently, the purpose of this study was to determine if monocyte functions and differentiation profiles differ in MS patients compared to healthy volunteers (HV) and whether pioglitazone can reverse these differences to promote CNS recovery.MethodsMonocytes were isolated from MS patients and HV (n ≥ 36/group), and their ability to phagocytose myelin and modulate inflammation in the presence/absence of 1 μmol/L pioglitazone (the in vivo achievable concentration) was quantified by flow cytometry, transcriptional profiling, and proteomic assays.Results MS monocytes display impaired phagocytosis of myelin debris and enhanced proinflammatory differentiation. Pioglitazone treatment causes partial normalization of identified monocyte abnormalities in MS and fully reverses the deficit in myelin phagocytosis.InterpretationThese findings suggest that by inhibiting proinflammatory differentiation of monocytes and enhancing their phagocytosis of myelin, pioglitazone may be a useful adjunct therapy to immunomodulatory agents that target dysregulated adaptive immunity in MS.

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis

“…As outlined further above, it is known that myelin debris is a major obstacle to neurorepair both as a physicospatial impediment via the expression of axon growth inhibitory molecules and also via an inhibition of OPC differentiation (18,(37)(38)(39). In doing so, myelin debris inhibits remyelination (18) so that this microglial core ability has recently become a new target for potential therapeutic approaches (40,41). Moreover, we observed that pHERV-W ENV stimulation led to a pronounced morphological shift to ameboid microglial phenotypes typical of proinflammatory activation already apparent after 1 and 2 d of pHERV-W ENV stimulation ( Fig.…”

Glatiramer acetate treatment normalized the monocyte activation profile in MS patients to that of healthy controls

“…Monocytes are also involved but can play a dual role by promoting or resolving inflammation depending on their activation state. 1 Recent studies have shown that circulating monocytes in MS patients resemble classically activated monocytes, [2][3][4] and this classical activation state is found on both of the major monocyte subsets. 3 Monocytes can be divided into two well-characterized subsets CD14 ++ CD16 − and CD14 + CD16 + monocytes.…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…The retinoid X receptor (RXR) plays an important role in monocyte/macrophage phagocytosis of myelin as suggested by pioglitazone-induced activation of peroxisome proliferatoractivated receptor c, one of the permissive binding partners of RXR, shown to inhibit pro-inflammatory differentiation of MS patient-derived monocytes/macrophages and to enhance myelin phagocytosis (Natrajan et al, 2015b). Moreover, the blockade of myelin debris clearance by microglia/macrophages in cuprizone-demyelinated CX3CR1-deficient mice, revealed the critical role played by CX3CR1, the receptor controlling microglial physiology and orchestrating the crosstalk between microglia and neurons (Lampron et al, 2015).…”