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Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion
Jason R Plemel1,2,3, Jo Anne Stratton1, Nathan J Michaels1
1Hotchkiss Brain Institute and Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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.
Insights
Microglia, the brain's immune cells, dominate CNS injury sites by proliferating and restricting peripheral macrophages. This interaction helps maintain the central nervous system's immune privilege.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- Microglia and infiltrating macrophages are key in the central nervous system (CNS) response to injury.
- Distinguishing their roles is difficult due to cellular similarities.
Purpose of the Study:
- To genetically differentiate microglia from infiltrating macrophages.
- To characterize microglia activation states and their interaction with macrophages during CNS injury.
Main Methods:
- Genetic labeling of microglia and macrophages.
- Single-cell RNA sequencing to analyze cell populations and activation states.
- In vivo studies in demyelinated CNS lesions and sciatic nerve models.
Main Results:
- Identified distinct microglia activation states, including interferon-associated signaling.
- Observed acute infiltration of blood-derived macrophages, followed by microglia monopolization of CNS lesions.
- Demonstrated sustained macrophage response in microglia-devoid sciatic nerve.
- Found microglia preferential proliferation and low death rates contribute to their dominance.
- Microglia ablation led to macrophage accumulation in demyelinated spinal cord, revealing a macrophage-microglia interaction.
Conclusions:
- Microglia play a dominant role in CNS lesion environments, partly through proliferation and spatial restriction of peripheral macrophages.
- This microglia-macrophage interaction may be a key mechanism for CNS immune privilege.
- Understanding these cellular dynamics is crucial for developing therapies for neurological injuries.
