TMEM106A deficiency in microglia attenuates functional recovery after spinal cord injury by exacerbating
1Department of Orthopedics, Affiliated Fuyang People's Hospital of Anhui Medical University, Fuyang, Anhui Province, China; National Key Clinical Specialty, Clinical Research Center for Spinal Deformity of Anhui Province, Fuyang, Anhui Province, China.
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.
Insights
Tetmem106a protein regulates microglial function after spinal cord injury (SCI). Loss of TMEM106A worsens inflammation and impairs recovery, highlighting its therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Spinal cord injury (SCI) causes permanent neurological deficits.
- Microglia play key roles in neuroinflammation and repair post-SCI.
- Molecular mechanisms controlling microglial function after SCI are not fully understood.
Purpose of the Study:
- To investigate the role of Tmem106a in microglial function and response to SCI.
- To determine if TMEM106A regulates microglial polarization and neuroinflammation.
Main Methods:
- Integrated bioinformatic analysis to identify upregulated genes post-SCI.
- Development of a microglia-specific Tmem106a conditional knockout (cKO) mouse model.
- Assessment of locomotor recovery using Basso Mouse Scale, swimming tests, and footprint analysis.
- Analysis of microglial phenotype (M1/M2 markers), inflammatory markers, neuronal apoptosis, and axonal regeneration.
Main Results:
- Tmem106a was significantly upregulated in microglia after SCI.
- Tmem106a cKO mice showed impaired locomotor recovery and exacerbated neuroinflammation.
- TMEM106A deficiency skewed microglia to a pro-inflammatory M1 phenotype, increasing NF-κB activation.
- TMEM106A deficiency led to elevated pro-inflammatory cytokines, increased neuronal apoptosis, and reduced axonal regeneration.
- TMEM106A overexpression attenuated inflammatory responses.
Conclusions:
- TMEM106A is a critical intrinsic regulator of microglial polarization.
- TMEM106A constrains neuroinflammation and promotes tissue repair after SCI.
- TMEM106A represents a potential therapeutic target for SCI treatment.
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