The role of CD11c+ microglia in post-ischemic stroke recovery - Project Summary/Abstract
Current treatment options for patients experienced ischemic stroke allow blood reperfusion to the brain but fails
to resolve the neurological deficits, which cause long-term physical and cognitive disabilities in stroke survivors.
Thus, novel therapeutic strategies for improving brain recovery and resolving neurological deficits are critically
needed. Neuronal death induces the activation of microglia that express proinflammatory mediators, leading to
the exacerbation of brain damage following ischemic stroke. Thus, targeting microglia was thought to ameliorate
brain injury post-stroke. However, recent studies have shown that the elimination of microglia increases the size
of brain infarct and worsens the neurological deficits of mice following transient middle cerebral artery occlusion
(tMCAO), an animal model for ischemic stroke studies. These data suggest a functional heterogeneity of
microglia in response to ischemic insults, or a temporal phenotypic shift of microglia from neurotoxic to
neuroprotective over time following ischemic injury. The goal of this proposal is to investigate whether the CD11c-
mediated signaling potentiates these diverse functions or phenotypical shift in microglia, and to determine the
potential neuroprotective role of CD11c+ microglia in brain recovery following ischemic stroke. CD11c is an
integrin alpha chain protein that is widely used as a defining marker for conventional dendritic cells (cDCs).
CD11c regulates cell adhesion, migration, and phagocytic activity of cDCs. The role of CD11c-mediated signaling
in microglia following ischemic stroke is not known. Transcriptome analysis suggests that CD11c+ microglia may
play a protective role following neurological insults, but experimental evidence to support this notion is lacking.
We performed tMCAO in Ccr2+/RFP x CD11c-EYFP mice, and observed a substantial increase of CD11c+
microglia in the brain following tMCAO. Our preliminary data have shown that 1) CD11c+ microglia mainly
appeared at the border of infract of the brain 72 hours following tMCAO. These microglia predominately co-
expressed the activation marker IBA-1; 2) CD11c+ IBA-1+ microglia migrated to and were maintained within the
glial scar 14 days following tMCAO; and 3) On day 14, a subset of CD11c+ IBA-1- microglia appears at the peri-
infarct area of the brain. In Aim 1, we hypothesize that CD11c expression in microglia promotes brain recovery
by directing the migration of microglia to the infarct core, and enhances their ability to eliminate dead cells. We
will address this hypothesis using CD11c-EYFP reporter mice crossed with CD11c-deficient mice. The role of
CD11c in microglia in promoting brain recovery following ischemic stroke will be further determined by single-
cell RNA sequencing. In Aim 2, we hypothesize that the elimination of CD11c+ microglia at the chronic phase
following ischemic injury increases brain infarct and exacerbates neurological deficits. We will test this hypothesis
using a bone marrow chimera strategy, in which tMCAO will be performed in mice that CD11c+ microglia are
selectively ablated. Elucidating the mechanisms by which microglia switch from proinflammatory to
neuroprotective can help develop novel strategies that promote neurological recovery following ischemic stroke.
