A recently published study in the Journal of Neuroinflammation has revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglial activation and exerts neuroprotective effects in the demyelination of neuromyelitis optica spectrum disorder (NMOSD).
The study found a significant increase in demyelination area due to TREM2 deficiency. In addition, the TREM2 deficiency also led to noneffective clearance and degradation of the myelin debris, signifying the critical role of TREM2 in remyelination in NMOSD.
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The researchers used AQP4-IgG and human complement to simulate NMOSD pathology. The study team analyzed the serum samples collected from 4 patients diagnosed with AQP4-IgG seropositive NMOSD. In addition, they also performed multiple experiments using TREM2−/− and WT mice to investigate the role of TREM2 in the pathological process of NMOSD.
Study results showed high expression of TREM2 on microglia/macrophages in the active demyelinating lesions. Moreover, it was observed that the TREM2 deficiency significantly increased the demyelination area. At the same time, the number of oligodendrocytes and mature oligodendrocytes decreased, and the proliferation of oligodendrocyte precursor cells was considerably weakened.
Additionally, the study demonstrated that TREM2 knockout damaged mice’s motor balance and coordination. Furthermore, recruitment and activation of TREM2-deficient microglia were significantly hindered, resulting in an inefficient clearance and degradation of the myelin debris, hence signifying the key role of TREM2 in remyelination in NMOSD.
“Our findings support that TREM2 is important for microglial activation and promotes microglial phagocytosis and degradation of myelin debris, playing a neuroprotective role during the demyelination of NMOSD,” the authors highlighted.
Neuromyelitis optica spectrum disorder is an inflammatory demyelinating disorder of the central nervous system (CNS) with over 80% of patients seropositive for immunoglobulin G (IgG) against aquaporin-4 (AQP4) on astrocytes. This autoantibody led to complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, resulting in demyelination, oligodendrocyte damage, and several neurological deficits in NMOSD.
Demyelination produces myelin debris that can obstruct the development of new oligodendrocytes, worsening demyelination and causing damage to axons. Microglia are immune cells in the CNS that help to remove this debris and promote the repair process. Prior studies have shown that microglia play a vital role in remyelination in multiple CNS diseases, including NMOSD.
TREM2 is a protein expressed on the microglia surface in CNS and plays a key role in regulating multiple immune responses in the CNS. This protein has reportedly been associated with the pathogenesis of numerous neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Research has shown that TREM2 acts as a sensor of the CNS microenvironment and regulates microglial activation, migration, and phagocytosis. Nonetheless, the explicit role of TREM2 in microglial activation and dysfunction in NMOSD is still limited.
Reference
You YF, Chen M, Tang Y, et al. TREM2 deficiency inhibits microglial activation and aggravates demyelinating injury in neuromyelitis optica spectrum disorder. J Neuroinflammation Published online April 3, 2023, doi: 10.1186/s12974-023-02772-3
