Role of Monocyte-Derived MicroRNA106b∼25 in Resilience to Social Stress

Madeline L. Pfau, Caroline Menard, Flurin Cathomas, Fiona Desland, Veronika Kana, Kenny L. Chan, Yusuke Shimo, Katherine LeClair, Meghan E. Flanigan, Hossein Aleyasin, Deena M. Walker, Sylvain Bouchard, Matthias Mack, Georgia E. Hodes, Miriam M. Merad, Scott J. Russo

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSDS), a mouse model of stress vulnerability that produces susceptible and resilient phenotypes. Methods: We isolated Ly6chigh monocytes via fluorescence-activated cell sorting in the blood of susceptible and resilient mice following RSDS and profiled miR expression via quantitative real-time polymerase chain reaction. Bone marrow chimeric mice were generated to confirm a causal role of the miR-106b∼25 cluster in bone marrow–derived leukocytes in mediating stress resilience versus susceptibility. Results: We found that RSDS produces an increase in circulating Ly6chigh inflammatory monocytes in both susceptible and resilient mice. We next investigated whether intrinsic leukocyte posttranscriptional mechanisms contribute to individual differences in stress response and the resilient phenotype. Of the miRs profiled in our panel, eight were significantly regulated by RSDS within Ly6chigh monocytes, including miR-25-3p, a member of the miR-106b∼25 cluster. Selective knockout of the miR-106b∼25 cluster in peripheral leukocytes promoted behavioral resilience to RSDS. Conclusions: Our results identify the miR-106b∼25 cluster as a key regulator of stress-induced inflammation and depression that may represent a novel therapeutic target for drug development.

Original languageEnglish (US)
Pages (from-to)474-482
Number of pages9
JournalBiological Psychiatry
Volume86
Issue number6
DOIs
StatePublished - Sep 15 2019
Externally publishedYes

Keywords

  • Immune system
  • Leukocyte
  • Major depressive disorder
  • microRNA
  • Resilience
  • Stress

ASJC Scopus subject areas

  • Biological Psychiatry

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