title: Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes.
abstract: Multiple 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.
  
  
  
  Monocytes 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.
  
  
  
  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.
  
  
  
  These 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.
authors.affiliation: Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland; Wellcome Trust-MRC Cambridge Stem Cell Institute University of Cambridge Cambridge CB2 0AH United Kingdom; Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0AH United Kingdom.
authors.forename: Muktha S
authors.initials: MS
authors.lastname: Natrajan
authors.affiliation: Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.
authors.forename: Mika
authors.initials: M
authors.lastname: Komori
authors.affiliation: Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Kosa
authors.affiliation: National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.affiliation: Wellcome Trust-MRC Cambridge Stem Cell Institute University of Cambridge Cambridge CB2 0AH United Kingdom; Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0AH United Kingdom.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: Neuroimmunological Diseases Unit National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bielekova
keywords: Anti‐inflammatory; monocytes; multiple sclerosis; myelin; pioglitazone