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GM-CSF-Producing B Cells Regulate Microglial Activation and Promote Microglial Transition to an Inflammation State in Experimental Autoimmune Encephalomyelitis Model Mice
44 Pages Posted: 11 Jun 2019
More...Abstract
B cells, which produce pro-inflammatory cytokines, have been implicated in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and are becoming therapeutic targets for MS/EAE. We analyzed the expression of GM-CSF-producing B (GM-CSF+B) cells in immune organs and the central nervous system (CNS) of EAE model mice at pre-clinical, clinical peak, and recovery stages. Selective B-cell Csf2 knock-out mice were produced and subjected to CNS-selective or systemic deletion of GM-CSF+B cells. GM-CSF+B cell deletion delayed EAE development and reduced EAE severity markedly. GM-CSF+B cell absence did not affect peripheral Th1/Th17 cell proportions, but was accompanied by reduced brain microglial activation. At the EAE clinical peak stage, 17 days postimmunization (dpi), microglia from GM-CSF+B cell-deficient EAE mice had reduced expression of microglial activation markers, increased expression of microglial homeostatic markers, and reduced expression of pro-inflammatory cytokines, relative to intact EAE mice. The condition was associated with increased levels of JAK/STAT signaling components. In conclusion, the present study suggests that GM-CSF+B cells are an important factor in triggering microglial activation during EAE pathogenesis. GM-CSF+B cell deletion reduced CNS microglial activation and pro-inflammatory cytokine production but did not affect Th1/Th17 differentiation. GM-CSF+B cell effects on microglia may be associated with JAK/STAT signaling. Our study is consistent with the notion that selective B cell subtype depletion is a warranted strategy in EAE/MS treatment.
Funding: This work was supported by the National Natural Science Foundation (grant number 81571168, 81430035, 81870955 and 81771035).
Declaration of Interest: The authors have no conflicting financial interests.
Ethical Approval: All animal handling and experimental procedures were performed in accordance with the guidelines of the Care and Use of Laboratory Animals published by the Chinese National Institute of Health.
Keywords: EAE, GM-CSF, B cells, microglia
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