CCR2 deficiency alters activation of microglia subsets in traumatic brain injury

Cell Rep. 2021 Sep 21;36(12):109727. doi: 10.1016/j.celrep.2021.109727.


In traumatic brain injury (TBI), a diversity of brain resident and peripherally derived myeloid cells have the potential to worsen damage and/or to assist in healing. We define the heterogeneity of microglia and macrophage phenotypes during TBI in wild-type (WT) mice and Ccr2-/- mice, which lack macrophage influx following TBI and are resistant to brain damage. We use unbiased single-cell RNA sequencing methods to uncover 25 microglia, monocyte/macrophage, and dendritic cell subsets in acute TBI and normal brains. We find alterations in transcriptional profiles of microglia subsets in Ccr2-/- TBI mice compared to WT TBI mice indicating that infiltrating monocytes/macrophages influence microglia activation to promote a type I IFN response. Preclinical pharmacological blockade of hCCR2 after injury reduces expression of IFN-responsive gene, Irf7, and improves outcomes. These data extend our understanding of myeloid cell diversity and crosstalk in brain trauma and identify therapeutic targets in myeloid subsets.

Keywords: CCR2; dendritic cells; innate immunity; macrophages; microglia; monocytes; neuroinflammation; single-cell RNA sequencing; traumatic brain injury; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Brain Injuries, Traumatic / metabolism
  • Brain Injuries, Traumatic / pathology*
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Humans
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / metabolism
  • Macrophages / cytology
  • Macrophages / metabolism
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / metabolism*
  • Monocytes / cytology
  • Monocytes / metabolism
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics*
  • Receptors, CCR2 / metabolism


  • Antigens, Ly
  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Irf7 protein, mouse
  • Ly-6C antigen, mouse
  • Receptors, CCR2