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Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin
Published on: March 26, 2015
Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis
Laura A N Peferoen1, Daphne Y S Vogel, Kimberley Ummenthum
1From the Departments of Pathology (LANP, DYSV, KU, WHG, RMBP-B, PvdV, SA) and Molecular Cell Biology and Immunology (DYSV, MB, PDAMH, CDD), VU University Medical Center, Amsterdam, The Netherlands; and Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine Dentistry, Queen Mary University of London, London, United Kingdom (SA).
Abstract:
Similar to macrophages, microglia adopt diverse activation states and contribute to repair and tissue damage in multiple sclerosis. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, we show that in vitro M1-polarized (proinflammatory) human adult microglia express the distinctive markers CD74, CD40, CD86, and CCR7, whereas M2 (anti-inflammatory) microglia express mannose receptor and the anti-inflammatory cytokine CCL22. The expression of these markers was assessed in clusters of activated microglia in normal-appearing white matter (preactive lesions) and areas of remyelination, representing reparative multiple sclerosis lesions. We show that activated microglia in preactive and remyelinating lesions express CD74, CD40, CD86, and the M2 markers CCL22 and CD209, but not mannose receptor. To examine whether this intermediate microglia profile is static or dynamic and thus susceptible to changes in the microenvironment, we polarized microglia into M1 or M2 phenotype in vitro and then subsequently treated them with the opposing polarization regimen. These studies revealed that expression of CD40, CXCL10, and mannose receptor is dynamic and that microglia, like macrophages, can switch between M1 and M2 phenotypic profiles. Taken together, our data define the differential activation states of microglia during lesion development in multiple sclerosis-affected CNS tissues and underscore the plasticity of human adult microglia in vitro.
Insights
Microglia, immune cells in the brain, show dynamic M1 and M2 activation states in multiple sclerosis lesions. These findings reveal microglia plasticity and potential therapeutic targets for central nervous system repair.
Area of Science:
- Neuroimmunology
- Cellular Biology
Background:
- Microglia, the resident immune cells of the central nervous system (CNS), exhibit diverse activation states similar to macrophages.
- These activation states contribute to both tissue repair and damage in neurological conditions like multiple sclerosis (MS).
Purpose of the Study:
- To define the differential activation states of microglia during lesion development in multiple sclerosis.
- To investigate the plasticity of human adult microglia and their potential to switch between M1 (proinflammatory) and M2 (anti-inflammatory) phenotypes.
Main Methods:
- Utilized reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry to analyze microglia markers.
- Assessed marker expression in microglia from normal-appearing white matter and active/reparative MS lesions.
- Performed in vitro polarization of human adult microglia to M1 or M2 phenotypes, followed by exposure to opposing polarization conditions.
Main Results:
- In vitro M1 microglia expressed CD74, CD40, CD86, and CCR7; M2 microglia expressed mannose receptor and CCL22.
- Activated microglia in preactive and remyelinating MS lesions displayed an intermediate profile, expressing M1 markers (CD74, CD40, CD86) and M2 markers (CCL22, CD209), but not mannose receptor.
- In vitro studies demonstrated that microglia can dynamically switch between M1 and M2 phenotypes, indicated by changes in CD40, CXCL10, and mannose receptor expression.
Conclusions:
- Human adult microglia exhibit distinct activation profiles during different stages of multiple sclerosis lesion development.
- Microglia possess significant phenotypic plasticity, capable of transitioning between M1 and M2 states, similar to macrophages.
- These findings highlight the dynamic nature of microglia in the MS CNS and offer insights into potential therapeutic strategies targeting microglia plasticity.
