Role for microglia in sex differences after ischemic stroke: importance of M2

Sheetal Bodhankar, Andrew Lapato, Yingxin Chen, Arthur Vandenbark, Julie Saugstad, Halina Offner

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Inflammation plays a critical role in the pathogenesis of ischemic stroke. This process depends, in part, upon proinflammatory factors released by activated resident central nervous system (CNS) microglia (MG). Previous studies demonstrated that transfer of IL-10+ B-cells reduced infarct volumes in male C57BL/6 J recipient mice when given 24 h prior to or therapeutically at 4 or 24 h after experimental stroke induced by 60 min middle cerebral artery occlusion (MCAO). The present study assesses possible sex differences in immunoregulation by IL-10+ B-cells on primary male vs. female MG cultured from naïve and ischemic stroke-induced mice. Thus, MG cultures were treated with recombinant (r)IL-10, rIL-4 or IL-10+ B-cells after lipopolysaccharide (LPS) activation and evaluated by flow cytometry for production of proinflammatory and anti-inflammatory factors. We found that IL-10+ B-cells significantly reduced MG production of TNF-α, IL-1β and CCL3 post-MCAO and increased their expression of the anti-inflammatory M2 marker, CD206, by cell-cell interactions. Moreover, MG from female vs. male mice had higher expression of IL-4 and IL-10 receptors and increased production of IL-4, especially after treatment with IL-10+ B-cells. These findings indicate that IL-10-producing B-cells play a crucial role in regulating MG activation, proinflammatory cytokine release and M2 phenotype induction, post-MCAO, with heightened sensitivity of female MG to IL-4 and IL-10. This study, coupled with our previous demonstration of increased numbers of transferred IL-10+ B-cells in the ischemic hemisphere, provide a mechanistic basis for local regulation by secreted IL-10 and IL-4 as well as direct B-cell/MG interactions that promote M2-MG.

Original languageEnglish (US)
Pages (from-to)1515-1529
Number of pages15
JournalMetabolic Brain Disease
Volume30
Issue number6
DOIs
StatePublished - Dec 1 2015

Fingerprint

Microglia
Sex Characteristics
Interleukin-10
Stroke
B-Lymphocytes
Cells
Interleukin-4
Middle Cerebral Artery Infarction
Cell Communication
Anti-Inflammatory Agents
Interleukin-10 Receptors
Chemical activation
Flow cytometry
Neurology
Interleukin-1
Lipopolysaccharides
Flow Cytometry
Demonstrations
Central Nervous System
Cytokines

Keywords

  • IL-10-secreting B-cells
  • M1 and M2 MG states
  • MCAO
  • Microglia

ASJC Scopus subject areas

  • Clinical Neurology
  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Role for microglia in sex differences after ischemic stroke : importance of M2. / Bodhankar, Sheetal; Lapato, Andrew; Chen, Yingxin; Vandenbark, Arthur; Saugstad, Julie; Offner, Halina.

In: Metabolic Brain Disease, Vol. 30, No. 6, 01.12.2015, p. 1515-1529.

Research output: Contribution to journalArticle

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abstract = "Inflammation plays a critical role in the pathogenesis of ischemic stroke. This process depends, in part, upon proinflammatory factors released by activated resident central nervous system (CNS) microglia (MG). Previous studies demonstrated that transfer of IL-10+ B-cells reduced infarct volumes in male C57BL/6 J recipient mice when given 24 h prior to or therapeutically at 4 or 24 h after experimental stroke induced by 60 min middle cerebral artery occlusion (MCAO). The present study assesses possible sex differences in immunoregulation by IL-10+ B-cells on primary male vs. female MG cultured from na{\"i}ve and ischemic stroke-induced mice. Thus, MG cultures were treated with recombinant (r)IL-10, rIL-4 or IL-10+ B-cells after lipopolysaccharide (LPS) activation and evaluated by flow cytometry for production of proinflammatory and anti-inflammatory factors. We found that IL-10+ B-cells significantly reduced MG production of TNF-α, IL-1β and CCL3 post-MCAO and increased their expression of the anti-inflammatory M2 marker, CD206, by cell-cell interactions. Moreover, MG from female vs. male mice had higher expression of IL-4 and IL-10 receptors and increased production of IL-4, especially after treatment with IL-10+ B-cells. These findings indicate that IL-10-producing B-cells play a crucial role in regulating MG activation, proinflammatory cytokine release and M2 phenotype induction, post-MCAO, with heightened sensitivity of female MG to IL-4 and IL-10. This study, coupled with our previous demonstration of increased numbers of transferred IL-10+ B-cells in the ischemic hemisphere, provide a mechanistic basis for local regulation by secreted IL-10 and IL-4 as well as direct B-cell/MG interactions that promote M2-MG.",
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AU - Offner, Halina

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