P75NTR blockading inhibits Trem2+ M1 phenotype microglia activation and myelin damage following mild traumatic brain injury

Abstract

The pathological basis underlying mild traumatic brain injury (mTBI)-induced long-term cognitive impairment is not fully understood. It is supposed that mTBI induces residential microglia activation rather than peripheral leukocyte infiltration to promote neuroinflammation, thus triggering myelin damage as well as cognitive impairment. The transformation of microglia towards a pro-inflammatory (M1 type) or anti-inflammatory (M2 type) state is critical for restraining the cerebral inflammatory response to acute or chronic insults. In addition to classical M1- and M2-like phenotypes, a specific subgroup of microglia, which is referred to as disease-associated microglia (DAM), the transition of which is regulated by triggering receptor expressed on myeloid cells 2 (Trem2), is also demonstrated to play a critical role in neurodegenerative diseases sharing similar pathological procedures to mTBI. The expression and function of p75 neurotrophin receptor (p75NTR) in microglia vary depending on the type and severity of the specific pathological stimuli. In the current study, we investigated whether peripheral leukocytes infiltrated the brain following mild traumatic brain injury (mTBI) using a CX3CR1- and CCR2-double transgenic reporter mouse model. We also examined whether M1- or M2-like microglia exhibited a disease-associated microglia (DAM) phenotype after mTBI, as indicated by their Trem2 expression. Then we explored the expression of p75NTR in M1- and M2-like phenotype microglia after mTBI and its modulating effects on the activation of Trem2 positive M1- and M2-like phenotype microglia, neuroinflammatory reaction, myelin damage, and cognitive performance. We found that most of the activated residential microglia after mTBI were Trem2 positive and p75NTR expression was significantly elevated in Trem2-positive M1-type microglia post-mTBI, correlating with increased pro-inflammatory cytokine release, demyelination, and cognitive deficits. Pharmacological blockade of p75NTR using the antagonist TAT-Pep5 suppressed M1 microglial activation, reduced neuroinflammation, and restored myelin integrity, leading to marked improvements in cognitive function. Mechanistically, p75NTR exhibited a cell-type-specific regulatory role in neuroinflammatory responses, potentially through interacting with Trem2 to modulate DAM-like microglia activation. These findings highlight p75NTR as a key mediator of mTBI-induced neuropathology and propose its inhibition as a novel therapeutic strategy to mitigate secondary neuroinflammation and cognitive decline.

Keywords: M1 microglia; Trem2; cognition deficit; mTBI; p75NTR.