Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion

Abstract

Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling. Although blood-derived macrophages acutely infiltrated the demyelinated lesion, microglia progressively monopolized the lesion environment where they surrounded infiltrating macrophages. In the microglia-devoid sciatic nerve, the infiltrating macrophage response was sustained. In the CNS, the preferential proliferation of microglia and sparse microglia death contributed to microglia dominating the lesion. Microglia ablation reversed the spatial restriction of macrophages with the demyelinated spinal cord, highlighting an unrealized macrophages-microglia interaction. The restriction of peripheral inflammation by microglia may be a previously unidentified mechanism by which the CNS maintains its “immune privileged” status.

The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury

“…Newly developed strategies to speci cally eliminate microglia, such as the use of PLX5622, a CSF1R inhibitor, demonstrated that the absence of microglia disrupts the organization of the astrocytic scar, reduces the number of neurons and oligodendrocytes at the site of injury, and impairs functional recovery after SCI [35]. Using targeted fate mapping, another recent study showed that microglia within the spinal lesion site respond heterogeneously, forming multiple activation states [36]. Further, the activated microglia can prevent the in ltration of peripheral macrophages and thereby prevent further white matter damage [36].…”

“…Using targeted fate mapping, another recent study showed that microglia within the spinal lesion site respond heterogeneously, forming multiple activation states [36]. Further, the activated microglia can prevent the in ltration of peripheral macrophages and thereby prevent further white matter damage [36]. These studies suggest that microglia are neuroprotective in the context of SCI.…”

The voltage-gated proton channel Hv1 contributes to neuronal injury and motor deficits in a mouse model of spinal cord injury

“…Newly developed strategies to speci cally eliminate microglia, such as the use of PLX5622, a CSF1R inhibitor, demonstrated that the absence of microglia disrupts the organization of the astrocytic scar, reduces the number of neurons and oligodendrocytes at the site of injury, and impairs functional recovery after SCI [39]. Using targeted fate mapping, another recent study showed that microglia within the spinal lesion site respond heterogeneously, forming multiple activation states [40]. Further, the activated microglia can prevent the in ltration of peripheral macrophages and thereby prevent further white matter damage [40].…”

“…Using targeted fate mapping, another recent study showed that microglia within the spinal lesion site respond heterogeneously, forming multiple activation states [40]. Further, the activated microglia can prevent the in ltration of peripheral macrophages and thereby prevent further white matter damage [40]. These studies suggest that microglia are neuroprotective in the context of SCI.…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…Single-cell RNA sequencing of microglia from LPC-mediated lesions revealed multiple gene expression profile clusters of activated microglia/macrophages sharing common genes such as apoE and unique genes such as Ccl4 or Cxcl10 according to the clusters (Hammond et al, 2019). Multiple activation states specifically reflecting microglia (and not macrophages) was also identified upon LPC-mediated demyelination suggesting that microglia can have multiple forms of activation likely identified by common or selective transcriptional programs (Plemel et al, 2020). Similarly, a specific ApoE-dependent molecular signature was identified in microglia/macrophages from different models of neurodegenerative diseases including EAE (Krasemann et al, 2017).…”