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Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes

Muktha S Natrajan1, Mika Komori2, Peter Kosa2

  • 1Neuroimmunological 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.

Annals of Clinical and Translational Neurology
|January 7, 2016
PubMed
Abstract

Insights

Multiple sclerosis monocytes show impaired myelin clearance and increased inflammation. Pioglitazone treatment partially normalizes these functions, fully restoring myelin phagocytosis in MS patients.

Area of Science:

  • Neuroimmunology
  • Cell Biology

Background:

  • Multiple sclerosis (MS) involves central nervous system (CNS) inflammation and demyelination.
  • Myeloid phagocytes, like monocytes, have a dual role in MS, potentially causing damage or promoting repair.
  • Retinoid X receptor (RXR) pathways are crucial for monocyte myelin phagocytosis.

Purpose of the Study:

  • To investigate differences in monocyte function and differentiation between MS patients and healthy volunteers (HV).
  • To determine if pioglitazone, a peroxisome proliferator-activated receptor γ agonist, can reverse MS-associated monocyte abnormalities.
  • To assess pioglitazone's potential to promote CNS recovery in MS.

Main Methods:

  • Monocytes were isolated from MS patients and HV (n ≥ 36/group).
  • Phagocytosis of myelin and inflammatory modulation were quantified using flow cytometry, transcriptional profiling, and proteomic assays.
  • Cells were treated with pioglitazone at an in vivo-achievable concentration (1 µmol/L).

Main Results:

  • Monocytes from MS patients exhibited impaired myelin debris phagocytosis and enhanced pro-inflammatory differentiation compared to HV.
  • Pioglitazone treatment partially normalized several identified monocyte abnormalities in MS.
  • Pioglitazone fully reversed the deficit in myelin phagocytosis observed in MS monocytes.

Conclusions:

  • MS monocytes display functional deficits that pioglitazone can partially ameliorate.
  • Pioglitazone enhances myelin phagocytosis and reduces pro-inflammatory differentiation in MS monocytes.
  • Pioglitazone may serve as an adjunctive therapy for MS, complementing treatments targeting adaptive immunity.
Keywords:
Anti‐inflammatorymonocytesmultiple sclerosismyelinpioglitazone

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