4.8 Article

CCR2 deficiency alters activation of microglia subsets in traumatic brain injury

Journal

CELL REPORTS
Volume 36, Issue 12, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2021.109727

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Funding

  1. Department of Veterans Affairs Biomedical Laboratory RD [BX002690]
  2. NIH [R00 HL135403, R01AR071522, R01AI136972, U01HG012192]
  3. National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR066735, P30AR070155]
  4. Russell/Engelman Rheumatology Research Center at UCSF
  5. United States Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service [I01 BX004115]
  6. Chan Zuckerberg Initiative
  7. Department of Veterans Affairs Biomedical Laboratory RD Merit Award [BX002994]
  8. S. Scott Panter Research Fund

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In traumatic brain injury, various types of myeloid cells play different roles in either exacerbating damage or assisting in healing. Through single-cell RNA sequencing analysis, multiple subsets of microglia, monocyte/macrophage, and dendritic cells were identified in acute TBI and normal brains, providing new therapeutic targets for brain trauma treatment.
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.

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