Traumatic brain injury induces macrophage subsets in the brain

Abstract

Summary Traumatic brain injury (TBI) elicits innate inflammatory responses that can lead to secondary brain injury. To better understand the mechanisms involved in TBI-induced inflammation, we examined the nature of macrophages responding to TBI in mice. In this model, brain macrophages were increased >20-fold the day after injury and >77-fold four days after injury in the ipsilateral hemisphere compared with sham controls. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an IRES inserted at the 3′ end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21±1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by YFP, and this subpopulation declined thereafter. Arg1+ cells localized with macrophages near the TBI lesion. Gene expression analysis of sorted Arg1+ and Arg1- brain macrophages revealed that both populations had profiles that included features of conventional M2 macrophages and classically activated (M1) macrophages. The Arg1+ cells differed from Arg1- cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI initially involves heterogeneous polarization towards at least two major subsets.

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

“…These data support other studies that evaluated macrophage and immune cell infiltration dynamics in TBI models. 30,31 Due to technical limitations when combining internalization staining protocols for M1-/M2-like markers with CD11b/CD45 cell surface markers, it was not possible to determine whether the infiltrating macrophages after were more M1-or M2-like polarized, but the peak in infiltration corresponded with high expression levels of both M1-and M2-like protein markers in this study.…”

“…30 Expression profiling of Arg1+ and Arg1-macrophage subpopulations that infiltrated after TBI revealed that they do not separate into true M1-or M2-like transcriptional profiles, but rather adopt mixed molecular phenotypes, and the ratio of macrophage subsets change over time after TBI. 30 Interestingly, blockade of macrophage infiltration by inhibiting CCR2 either by genetic or pharmacological means improves outcomes after TBI. Compared with wild-type mice, CCR2 knockout mice subjected to CCI have reduced lesion volumes, decreased pro-inflammatory gene expression, decreased macrophage infiltration in the injured cortex and improved cognitive function recovery after TBI.…”

CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

“…[46][47][48] To determine the role of CCR2 in monocyte recruitment, we performed TBI in Ccr2 -/ -mice and analyzed the presence of macrophages in the brain. Immunohistochemistry for F4/80 antigen, a marker on both macrophages and microglia, was performed at day 4, a time point where we observed peak macrophage infiltration in this model.…”

Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

“…They, like in other works, see robust Arg1 upregulation early after injury, with distinct Arg1 positive and negative populations (Hsieh et al, 2013). However, after sorting cells based on YFP and analyzing their transcription profiles they found that…”

“…Arg1 positive cells, which should be M2, do not express many other M2 markers and actually express some M1 markers (Hsieh et al, 2013). These findings are not necessarily surprising, Figure 2.3: Beneficial and detrimental roles for macrophages and neutrophils in CNS injury.…”