Abstract
BackgroundTraumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. However, its function in regulating the innate immune response and microglial/macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI.MethodsThe controlled cortical impact (CCI) mouse model was employed. Mer siRNA was intracerebroventricularly administered, and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed.ResultsMer is upregulated and regulates microglial/macrophage M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial/macrophage M2-like polarization while increases M1-like polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation.ConclusionsMer is an important regulator of microglial/macrophage M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide
We found that inhibition of Myeloid-epithelial-reproductive tyrosine kinase (Mer) shifts microglial/macrophage polarization toward the M1-like phenotype via regulating the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway, which exacerbates neuroinflammation and secondary brain damage following TBI
Dynamic changes in mRNA expression of microglial/ macrophage M1/M2 polarization markers following TBI Polarized microglia/macrophages can be commonly distinguished by their expression profiles of signature surface markers and cytokines/chemokines
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/ macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Its function in regulating the innate immune response and microglial/ macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI. Traumatic brain injury (TBI) is a devastating neurological disease and a major cause of death and disability worldwide, young people and the elderly [1, 2]. A comprehensive understanding of this notorious disease is still lacking, and the need for therapeutics that effectively improve long-term functional outcomes in TBI survivors remains unmet
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