Interleukin-10 Prevents Pathological Microglia Hyperactivation following Peripheral Endotoxin Challenge

Anat Shemer, Isabelle Scheyltjens, Gal Ronit Frumer, Jung-Seok Kim, Jonathan Grozovski, Serkalem Ayanaw, Bareket Dassa, Hannah Van Hove, Louise Chappell-Maor, Sigalit Boura-Halfon, Dena Leshkowitz, Werner Mueller, Nicola Maggio, Kiavash Movahedi, Steffen Jung

Research output: Contribution to journalArticlepeer-review

Abstract

Microglia, the resident macrophages of the brain parenchyma, are key players in central nervous system (CNS) development, homeostasis, and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain quiescence following challenges remains less understood. Here, we explored the role of the interleukin-10 (IL-10) axis in restoring murine microglia homeostasis following a peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia displayed neuronal impairment and succumbed to fatal sickness. Addition of a microglial tumor necrosis factor (TNF) deficiency rescued these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing immune cells in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation.

Original languageEnglish
Pages (from-to)1033-1049.e7
JournalImmunity
Volume53
Issue number5
Early online date12 Oct 2020
DOIs
StatePublished - 17 Nov 2020

Keywords

  • Cx3cr1
  • IL-10
  • LPS
  • LTP
  • Microglia activation
  • TNF
  • conditional mutagenesis
  • sepsis
  • sickness behavior
  • tamoxifen

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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