Soluble TREM-2: Tracking Microglial Activity and Treatment Response in Multiple Sclerosis

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease. It starts as an immune system misfire—where the body mistakenly attacks the protective myelin sheath surrounding nerve fibers in the brain and spinal cord—and evolves over time into a process marked by chronic inflammation and neurodegeneration. One of the key players in this late-stage neurodegeneration is microglia, the brain’s resident immune cells.

A study by Öhrfelt et al. (2016) shines a spotlight on a potential new biomarker of microglial activity in MS: soluble TREM-2 (sTREM-2) in cerebrospinal fluid (CSF). Not only does this molecule help us understand disease processes better, but it also responds to treatment—suggesting possible use in monitoring therapy effectiveness.

What is TREM-2 and Why Does it Matter?
TREM-2 (Triggering Receptor Expressed on Myeloid cells-2) is a receptor found mainly on microglia in the brain. When activated, it seems to dampen inflammation and help microglia clear away cellular debris, including damaged myelin. Think of it as part of the brain’s cleanup crew—important for both limiting damage and promoting repair.

When TREM-2’s external portion is cut off (a process called ectodomain shedding), it appears in the CSF as soluble TREM-2 (sTREM-2). Measuring this soluble form can give researchers a clue about how active microglia are in the brain.

The Study: Measuring sTREM-2 in MS Patients
The researchers analyzed CSF samples from:

59 people with MS:

36 with relapsing-remitting MS (RRMS)

20 with secondary progressive MS (SPMS)

3 with primary progressive MS (PPMS)

27 healthy controls

They also looked at how sTREM-2 levels changed after treatment with two potent MS drugs:

Natalizumab – a monoclonal antibody that stops immune cells from entering the brain and spinal cord.

Mitoxantrone – a chemotherapy-derived drug that broadly suppresses immune function. Key Findings
Higher sTREM-2 in All MS Types
At baseline, people with RRMS, SPMS, and PPMS all had significantly higher sTREM-2 levels compared to healthy controls. This suggests that microglial activation is a common feature across different stages of MS.

Treatment Effects
Natalizumab: After 12 months, sTREM-2 levels dropped to normal (control) levels. Patients also showed clinical improvement, with lower disability scores (EDSS and MSSS).

Mitoxantrone: After 24 months, sTREM-2 levels fell but remained above control levels. Disability scores didn’t improve, even though some biochemical signs of reduced damage were present.

Disease Duration Links
sTREM-2 levels tended to be higher earlier in the disease and decreased as the disease progressed, especially in RRMS. In SPMS, sTREM-2 was linked to greater disease severity.

Why This Matters
This research suggests that sTREM-2 could serve as:

A biomarker of microglial activation in MS—valuable for understanding disease activity beyond what MRI scans can show.

A treatment-response marker, particularly in therapies like natalizumab that strongly reduce inflammation in the brain.

A potential bridge biomarker between neuroinflammation and neurodegeneration, helping researchers track when the disease shifts from one process to the other.

It’s important to note, however, that sTREM-2 is not MS-specific—it’s elevated in other neurological inflammatory conditions too. This limits its diagnostic value but still makes it powerful for disease monitoring.

Limitations and Future Directions
The study didn’t include a placebo group, so some changes might be due to natural disease fluctuations. Also, the variability of the assay used to measure sTREM-2 means it’s not yet ready for routine clinical use.

Future research will need to refine the measurement techniques and explore how sTREM-2 behaves in response to other MS therapies, or even as part of combination biomarker panels alongside markers like neurofilament light (NFL).

Bottom Line
Öhrfelt and colleagues have provided compelling evidence that soluble TREM-2 in the CSF is elevated in all forms of MS and can be brought closer to normal by effective anti-inflammatory treatment, particularly natalizumab. While not a silver-bullet diagnostic tool, sTREM-2 is emerging as a promising biomarker for tracking microglial activity and potentially guiding therapy decisions.

In the evolving world of MS research, this is another step toward making invisible processes—like microglial activation—measurable and, eventually, targetable.

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:
Öhrfelt, A., Axelsson, M., Malmeström, C., Novakova, L., Heslegrave, A., Blennow, K., ... & Zetterberg, H. (2016). Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Multiple Sclerosis Journal, 22(12), 1587-1595.