Summary: New research shows that microglia — the brain’s resident immune cells — can block blood-derived macrophages from spreading into damaged areas of the central nervous system. This insight may guide development of therapies for multiple sclerosis, Alzheimer’s disease, spinal cord injury and other neurodegenerative conditions.
Source: University of Alberta
Unexpected findings from a collaborative study reveal how microglia shape immune responses after demyelination in the central nervous system.
Researchers led by Jason Plemel at the University of Alberta, with collaborators Joanne Stratton (McGill University), Wee Yong and Jeff Biernaskie (University of Calgary), report that microglia interfere with blood-derived immune cells called macrophages, limiting their movement into areas of CNS damage. This discovery clarifies a previously unrecognized interaction between resident and infiltrating immune cells and suggests new directions for treating diseases that involve myelin loss and neuroinflammation.
Microglia are the central nervous system’s resident immune cells, while macrophages typically arrive from the bloodstream in response to injury or inflammation. The team found that, rather than coexisting freely in damaged tissue, microglia tend to surround and encapsulate infiltrating macrophages. “We expected macrophages to move into injured areas, but what surprised us was that microglia formed a tight barrier around them — almost like police containing a crowd,” said Plemel. “It appears microglia can prevent macrophages from dispersing into regions where they might otherwise migrate.”
“When we removed microglia experimentally to determine their role, macrophages spread into previously uninjured tissue,” explained Plemel, who is also a member of the Neuroscience and Mental Health Institute.
The central nervous system contains white matter and grey matter. White matter consists of axons wrapped in myelin, the insulating layer that accelerates electrical signaling between cells. In many neurological disorders, including multiple sclerosis, Alzheimer’s disease and traumatic spinal cord injury, myelin becomes damaged or lost (demyelination), exposing nerve fibers to further injury and degeneration.
The researchers show that both microglia and infiltrating macrophages arrive early after demyelination, but microglia progressively accumulate and dominate the lesion environment. This microglial dominance appears to limit the spread of macrophages throughout the tissue. In contrast, when peripheral nerves outside the CNS are injured — for example, in the sciatic nerve of the leg — macrophages accumulate more freely without a comparable resident cell barrier, highlighting a unique CNS-specific immune behavior.
Distinguishing microglia from infiltrating macrophages has historically been challenging because the cells share many features. The new genetic labeling and single-cell analysis techniques used by the team allowed them to identify and track each population separately, revealing how microglia actively restrict macrophage dispersion in demyelinated regions.
Importantly, the study also identified heterogeneity among microglia themselves. Using single-cell RNA sequencing, the researchers found multiple activation states of microglia in response to acute demyelination, including a population enriched for interferon-associated signaling. “The presence of at least two distinct microglial populations is an exciting finding,” said Plemel. “Understanding how these subpopulations differ in function could reveal why the CNS mounts a different immune response than peripheral tissues and how that response could be modulated for therapy.”
These results raise important questions about why microglia form a containment barrier and how this behavior influences repair, inflammation resolution, and long-term outcomes after injury. If microglia serve to limit peripheral inflammation and preserve aspects of the CNS’s immune-privileged status, manipulating microglial activity or selectively modulating macrophage access could become a therapeutic strategy for demyelinating and neurodegenerative diseases.
Source:
University of Alberta
Media Contact:
Ross Neitz – University of Alberta
Image Source:
The image is in the public domain.
Original Research (open access):
“Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion,” Jason Plemel et al., Science Advances. DOI: 10.1126/sciadv.aay6324
Abstract (summary):
The study used genetic labeling and single-cell transcriptomics to separate microglia and CNS-associated macrophages from infiltrating macrophages during acute demyelination. The authors describe multiple microglial activation states, note early infiltration of blood-derived macrophages, and show microglia progressively monopolize the lesion and surround infiltrating macrophages. In peripheral nerves lacking microglia, macrophage responses are more sustained; in the CNS, preferential microglial proliferation and low microglial death contribute to lesion dominance. Ablation of microglia removed the spatial restriction of macrophages in the demyelinated spinal cord, revealing a previously unappreciated microglia–macrophage interaction that may help explain aspects of CNS immune privilege.