Cell Reports (Sep 2021)
CCR2 deficiency alters activation of microglia subsets in traumatic brain injury
- Kerri Somebang,
- Joshua Rudolph,
- Isabella Imhof,
- Luyi Li,
- Erene C. Niemi,
- Judy Shigenaga,
- Huy Tran,
- T. Michael Gill,
- Iris Lo,
- Brian A. Zabel,
- Gabriela Schmajuk,
- Brian T. Wipke,
- Stefka Gyoneva,
- Luke Jandreski,
- Michael Craft,
- Gina Benedetto,
- Edward D. Plowey,
- Israel Charo,
- James Campbell,
- Chun Jimmie Ye,
- S. Scott Panter,
- Mary C. Nakamura,
- Walter Eckalbar,
- Christine L. Hsieh
Affiliations
- Kerri Somebang
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Joshua Rudolph
- School of Medicine, Lung Biology Center, Division of Pulmonology, UCSF, San Francisco, CA, USA
- Isabella Imhof
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Luyi Li
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Erene C. Niemi
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Judy Shigenaga
- San Francisco VA Health Care System, San Francisco, CA, USA; Department of Medicine, Division of Endocrinology and Metabolism, UCSF, San Francisco, CA, USA
- Huy Tran
- San Francisco VA Health Care System, San Francisco, CA, USA
- T. Michael Gill
- Gladstone Institutes, San Francisco, CA, USA
- Iris Lo
- Gladstone Institutes, San Francisco, CA, USA
- Brian A. Zabel
- Palo Alto Veterans Institute for Research, Palo Alto, CA, USA; Palo Alto VA Health Care System, Palo Alto, CA, USA
- Gabriela Schmajuk
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Brian T. Wipke
- Biogen, Cambridge, MA, USA
- Stefka Gyoneva
- Biogen, Cambridge, MA, USA
- Luke Jandreski
- Biogen, Cambridge, MA, USA
- Michael Craft
- Biogen, Cambridge, MA, USA
- Gina Benedetto
- Biogen, Cambridge, MA, USA
- Edward D. Plowey
- Biogen, Cambridge, MA, USA
- Israel Charo
- ChemoCentryx, Mountain View, CA, USA
- James Campbell
- ChemoCentryx, Mountain View, CA, USA
- Chun Jimmie Ye
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Institute for Human Genetics, Department of Epidemiology and Biostatistics, Institute of Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA
- S. Scott Panter
- San Francisco VA Health Care System, San Francisco, CA, USA; Department of Neurological Surgery, UCSF, San Francisco, CA, USA
- Mary C. Nakamura
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA
- Walter Eckalbar
- School of Medicine, Lung Biology Center, Division of Pulmonology, UCSF, San Francisco, CA, USA
- Christine L. Hsieh
- Department of Medicine, Division of Rheumatology, University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco VA Health Care System, San Francisco, CA, USA; Corresponding author
- Journal volume & issue
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Vol. 36,
no. 12
p. 109727
Abstract
Summary: 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.
