CCR2 deficiency alters activation of microglia subsets in traumatic brain injury.

Kerri Somebang,Joshua Rudolph,Edward D Plowey,S Scott Panter,Gabriela Schmajuk,Michael Craft,Stefka Gyoneva,Christine L Hsieh,Iris Lo,Isabella Imhof,Luke Jandreski,Luyi Li,Brian T Wipke,Gina Benedetto,Chun Jimmie Ye,Mary C Nakamura,Brian A Zabel,Walter L Eckalbar ,Judy K Shigenaga ,James J Campbell ,Israel F Charo ,Thomas M Gill ,Eréne C Niemi ,Huy T Tran

doi:10.1016/j.celrep.2021.109727

Abstract

SUMMARYIn 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.

Highlights

Traumatic brain injury (TBI) is a significant public health issue in the United States (US)
We previously demonstrated that mice deficient in C-C chemokine receptor-2 (Ccr2) exhibit reduced macrophage infiltration, improved hippocampal-dependent cognitive outcomes, and preserved viable hippocampal neurons (Hsieh et al, 2014)
Single-cell RNA sequencing identifies cell lineages and subtypes in the acute TBI brain We previously showed that Ccr2À/À male mice demonstrated improvements in memory and histopathology following TBI, compared to wild-type (WT) mice (Hsieh et al, 2014)

Summary

Introduction

Traumatic brain injury (TBI) is a significant public health issue in the United States (US). TBI often leads to lifelong motor, cognitive, and behavioral disabilities (Potts et al, 2006; Elder, 2015). It is a risk factor for developing other neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (Elder, 2015). The responding circulating immune cells include monocyte-derived macrophages, which infiltrate the brain and differentiate into activated macrophages within and around the area of injury. Resident innate immune cells, including microglia, become activated at the injury site (Jassam et al, 2017).

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