Minocycline Selectively Inhibits M1 Polarization of Microglia

Cell Death Dis. 2013 Mar 7;4(3):e525. doi: 10.1038/cddis.2013.54.

Abstract

Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1(G93A) mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1(G93A) mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / mortality
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • B7-2 Antigen / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Inflammation / metabolism
  • Interleukin-4 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Microglia / cytology
  • Microglia / drug effects*
  • Microglia / metabolism
  • Minocycline / pharmacology*
  • NF-kappa B / metabolism
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Survival Rate
  • Up-Regulation

Substances

  • Aif1 protein, mouse
  • Anti-Bacterial Agents
  • B7-2 Antigen
  • Calcium-Binding Proteins
  • Lipopolysaccharides
  • Microfilament Proteins
  • NF-kappa B
  • SOD1 protein, human
  • Interleukin-4
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Minocycline