Macrophages in Multiple Sclerosis: The Agents of the Brain’s Immune System
When most people think of multiple sclerosis (MS), they imagine an immune system gone rogue—T cells attacking the protective myelin sheaths around neurons. But this is only part of the story.
Recent research has revealed that macrophages—the immune system’s garbage collectors and peacekeepers—play a surprisingly dual role in MS. Depending on their activation state, they can either worsen inflammation and tissue damage or promote repair and regeneration.
This duality makes macrophages both culprits and healers in the pathogenesis of MS.
The Many Faces of Macrophages
Macrophages are highly adaptable cells of the innate immune system. In the brain and spinal cord, they exist in two main forms:
Microglia – the brain’s resident macrophages, originating from embryonic yolk sac progenitors.
Monocyte-derived macrophages – immune cells recruited from the blood during inflammation.
Both types maintain CNS homeostasis under normal conditions but can switch into inflammatory warriors when things go wrong.
Scientists often categorize macrophages into two simplified states:
M1 macrophages – pro-inflammatory, releasing nitric oxide (NO), IL-1β, TNF-α, and other cytokines that exacerbate tissue damage.
M2 macrophages – anti-inflammatory and reparative, promoting remyelination and secreting growth factors like TGF-β and IGF-1.
Of course, this M1/M2 dichotomy is an oversimplification. In reality, macrophages exist on a functional spectrum, responding to complex environmental cues within the CNS.
Microglia: The Brain’s Watchdogs
Microglia are among the first responders to CNS injury. In healthy brains, they continuously survey their surroundings using specialized receptors like P2RY12 and CX3CR1, communicating with neurons via fractalkine signaling.
When danger signals appear—whether from infection, trauma, or demyelination—microglia transform. Their shape changes from ramified to amoeboid, and they begin to produce inflammatory mediators and reactive oxygen species (ROS).
This response, while meant to protect, can also fuel neurodegeneration if left unchecked. Indeed, clusters of activated microglia (known as microglial nodules) are often found near MS lesions.
Monocyte-Derived Macrophages: Reinforcements or Invaders?
During active MS, monocytes infiltrate the CNS, guided by adhesion molecules (like VCAM-1 and VLA-4) and chemokines (CCL2, CCL5, etc.). Once inside, they differentiate into macrophages that can:
Present antigens to T cells
Release inflammatory cytokines
Generate nitric oxide, leading to demyelination and axonal injury
Yet, under the right conditions, these same cells can flip their phenotype, becoming M2-type macrophages that clear myelin debris, secrete IL-10 and TGF-β, and encourage remyelination.
Therapeutic Targeting: Modulating the Macrophage Balance
Given their dual roles, macrophages are increasingly seen as therapeutic targets in MS. Several disease-modifying therapies (DMTs) already influence these cells—sometimes unintentionally.
Current DMTs That Affect Macrophages and Microglia
Interferon-beta (IFN-β): Enhances microglial phagocytosis of myelin debris and reduces monocyte migration into the CNS.
Glatiramer acetate (Copaxone): Promotes anti-inflammatory macrophages, boosting IL-10 and TGF-β while suppressing TNF-α and IL-12.
Fingolimod (FTY720): Shifts microglia from M1 to M2 phenotypes, dampening inflammation.
Natalizumab: Blocks VLA-4, reducing immune cell infiltration into the CNS.
Dimethyl fumarate (Tecfidera): Lowers pro-inflammatory microRNA-155 and promotes anti-inflammatory macrophage states.
These therapies, while developed to modulate lymphocytes, have important off-target benefits in reprogramming macrophage responses.
Emerging Therapies and Future Directions
New experimental strategies are now focusing directly on macrophage modulation. For instance:
Blocking ninjurin-1, a molecule guiding monocyte migration, reduces immune cell infiltration and demyelination in animal models.
Galectin-1 treatment inhibits pro-inflammatory microglial activation.
Thymoquinone (from Nigella sativa) downregulates NF-κB signaling and inflammatory cytokines in microglia.
M-CSF promotes anti-inflammatory microglia expressing TREM2, a receptor essential for debris clearance.
Progesterone and ivermectin have shown potential in enhancing remyelination and microglial M2 polarization.
The ultimate goal? To tilt the M1/M2 balance toward a neuroprotective, regenerative state—without compromising the immune system’s defense mechanisms.
Conclusion: Rethinking MS Through the Macrophage Lens
The emerging evidence paints macrophages and microglia not as mere bystanders but as key orchestrators of MS pathology and repair. Their ability to oscillate between destructive and restorative modes gives researchers a unique therapeutic opportunity.
By learning how to reprogram macrophages—encouraging their healing side while silencing their inflammatory impulses—we may one day move closer to halting, or even reversing, the damage caused by multiple sclerosis.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Radandish, M., Khalilian, P., & Esmaeil, N. (2021). The role of distinct subsets of macrophages in the pathogenesis of MS and the impact of different therapeutic agents on these populations. Frontiers in immunology, 12, 667705.
