Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus

• Published in: Brain, behavior, and immunity behavior, and immunity, 2025-01, Vol.123, p.540-555
• Main Authors: Bosco, Dale B., Kremen, Vaclav, Haruwaka, Koichiro, Zhao, Shunyi, Wang, Lingxiao, Ebner, Blake A., Zheng, Jiaying, Xie, Manling, Dheer, Aastha, Perry, Jadyn F., Barath, Abhijeet, Nguyen, Aivi T., Worrell, Gregory A., Wu, Long-Jun
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; CD68; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe - genetics; Epilepsy, Temporal Lobe - metabolism; Humans; Kainic Acid; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; Neurons - metabolism; Phagocytosis; Phagocytosis - genetics; Phagocytosis - physiology; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Seizures; Seizures - genetics; Seizures - metabolism; Status Epilepticus - genetics; Status Epilepticus - metabolism; TREM2
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2024.09.034

[Display omitted] •TREM2 deficiency significantly promoted acute status epilepticus and spontaneous recurrent seizures in mice.•TREM2 deficiency impaired phagocytic clearance of damaged neurons by microglia.•There was negative correlation between microglial CD68 expression and generalized seizure in human patients. In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute status epilepticus and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.