TMEM106A deficiency in microglia attenuates functional recovery after spinal cord injury by exacerbating neuroinflammation.

Abstract

Spinal cord injury (SCI) is a devastating condition that leads to permanent neurological deficits. SCI is characterized by a primary injury followed by a complex secondary injury phase in which microglia, the resident immune cells of the central nervous system, are pivotal players in neuroinflammation and repair. However, the molecular mechanisms controlling the microglial biofunction remain incompletely understood. Herein, through integrated bioinformatic analysis, we discovered that Tmem106a is significantly upregulated after SCI, and highly expressed in microglia. To investigate its role, a microglia-specific Tmem106a conditional knockout (cKO) mouse model was developed. After contusive SCI, Tmem106a cKO mice exhibited worse locomotor recovery, as assessed by the Basso Mouse Scale, swimming tests, and footprint analysis. This impaired functional outcome was driven by exacerbated neuroinflammatory response. We found that TMEM106A deficiency skewed microglia towards a pro-inflammatory M1-like phenotype, with increased iNOS and decreased Arg1 expression, while amplifying NF-κB pathway activation. This shift was associated with elevated pro-inflammatory cytokines, enhanced neuronal apoptosis, and impaired axonal regeneration. Conversely, TMEM106A overexpression in microglia attenuated LPS-induced inflammatory responses. Collectively, our findings indicate that TMEM106A is an essential intrinsic regulator of microglial polarization that constrains neuroinflammation and promotes tissue repair after SCI suggesting it as a therapeutic target.