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Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity

Björn Ambrosius1, Simon Faissner2,3, Kirsten Guse2,4

  • 1Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. Bjoern.Ambrosius@ruhr-uni-bochum.de.

Journal of Neuroinflammation
|March 13, 2017
PubMed

Insights

Teriflunomide and monomethylfumarate reduce neurotoxic inflammation in HIV-associated neurocognitive disorders (HAND). These drugs decrease pro-inflammatory cytokines and protect human fetal neurons from toxicity, offering potential treatments for HAND.

Area of Science:

  • Neuroimmunology
  • Virology
  • Pharmacology

Background:

  • HIV-associated neurocognitive disorders (HAND) affect approximately 50% of patients despite treatment.
  • Ongoing inflammation, driven by HIV-infected monocytes activating microglia, is implicated in HAND neurotoxicity.
  • Viral replication is not the sole driver of HAND-related neuroinflammation.

Purpose of the Study:

  • To investigate the effects of teriflunomide and monomethylfumarate on monocyte/microglial activation.
  • To assess the impact of these drugs on neurotoxicity in a HAND model.
  • To determine if these compounds can modulate pro-inflammatory cytokine secretion.

Main Methods:

  • Co-culture of HIV-Vector transduced U937 cells with human microglial cells (HMC3).
  • Treatment of co-cultures with teriflunomide and monomethylfumarate.
  • Measurement of pro-inflammatory/neurotoxic cytokine secretion (CXCL10, CCL5, CCL2, IL-6).
  • Assessment of conditioned media toxicity on human fetal neurons.

Main Results:

  • Co-cultures significantly increased secretion of CXCL10, CCL5, CCL2, and IL-6 compared to microglia alone.
  • Teriflunomide decreased secretion of CXCL10 (3-fold), CCL2 (2.5-fold), and IL-6 (2.2-fold).
  • Monomethylfumarate reduced CXCL10 secretion by 2.9-fold.
  • Both drugs significantly reduced the toxicity of conditioned media on human fetal neurons.

Conclusions:

  • Teriflunomide and monomethylfumarate effectively reduce pro-inflammatory cytokine secretion in an in vitro model of HAND.
  • These drugs demonstrate functional relevance by decreasing neurotoxicity.
  • Modulation of innate immune responses by teriflunomide and monomethylfumarate presents a potential therapeutic strategy for HAND-related neuroinflammation.
Keywords:
Dimethyl fumarateGlial activationHANDHIV-associated neurocognitive disorderLeflunomideMicrogliaNeuroinflammation

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