Through the Regulation of the TRAF5-MAPK Signaling Pathway in Microglial Polarization, CD36 Inhibits and Alleviates White Matter Damage After Traumatic Brain Injury

Research Background

Traumatic brain injury (TBI) not only damages gray matter but also causes severe white matter damage. White matter damage results in a significant loss of oligodendrocytes, disrupting the formation and maintenance of myelin sheaths, interfering with axonal metabolism and the regulation of neuronal plasticity, ultimately leading to severe neurological dysfunction. Currently, there is more research on treatments for gray matter damage, while studies on white matter damage are relatively few, which may partly explain the poor clinical outcomes. The inflammatory response is a major pathological process in secondary damage after TBI, with activated microglia playing a key role. The activation of microglia is accompanied by phenotypic polarization, which can be divided into pro-inflammatory and anti-inflammatory phenotypes. Pro-inflammatory microglia release large amounts of inflammatory factors, exacerbating neuronal damage, whereas anti-inflammatory microglia facilitate neural repair. Therefore, regulating microglial phenotypic polarization is expected to become a potential new strategy for treating white matter damage.

The CD36 receptor plays an important role in many central nervous system diseases, but its mechanism in white matter damage and microglial polarization after TBI is still unclear. This study aims to elucidate the functional role and molecular mechanism of CD36 in regulating microglial polarization and white matter damage.

Research Methods

This study established a mouse controlled cortical impact (CCI) model and used techniques such as Western blot, qPCR, and immunofluorescence to detect the spatiotemporal expression pattern of CD36 after TBI. Methods such as transmission electron microscopy and luxol fast blue staining were used to assess the degree of white matter damage. Transcriptome sequencing and bioinformatics analysis were applied to clarify the protective effect of CD36 downregulation on white matter damage and its molecular mechanism. Western blot, qPCR, and immunofluorescence were used to detect the polarization state of microglia. In vivo and in vitro experiments involved using CD36, TRAF5 siRNA knockdown, or small molecule inhibitors to inhibit the MAPK pathway to explore the regulatory role of the CD36-TRAF5-MAPK axis on microglial polarization and white matter damage. Furthermore, an in vitro co-culture system of BV2 cells and oligodendrocytes was used to verify the effect of CD36-regulated microglial polarization on oligodendrocyte damage.

Main Findings

1. CD36 reached peak expression on the 7th day after TBI, mainly located in astrocytes and microglia.

2. CD36 gene knockout alleviated myelin loss and oligodendrocyte damage, improving neurological deficits in mice after TBI.

3. Transcriptome sequencing results showed that differentially expressed genes after CD36 gene knockout were mainly enriched in biological processes related to microglial activation, neuroinflammation regulation, and the TNF signaling pathway.

4. CD36 knockdown inhibited the polarization of microglia to the pro-inflammatory phenotype and increased the anti-inflammatory phenotype; this mechanism is related to the inhibition of the downstream TRAF5-MAPK signaling pathway.

5. Inhibition of TRAF5 or p38 MAPK mimicked the anti-inflammatory effects produced by CD36 deficiency.

6. In the co-culture system, the supernatant from CD36-knockdown BV2 cells reduced oligodendrocyte damage induced by hypoxia and glucose deprivation, enhancing their survival and differentiation ability.

Research Significance

This study is the first to elucidate the key role and molecular mechanism of the CD36 receptor in white matter damage after TBI. CD36 can regulate microglial polarization through the TRAF5-MAPK signaling pathway, inhibiting the pro-inflammatory phenotype and promoting the anti-inflammatory phenotype, thereby reducing white matter damage. This discovery not only enriches our understanding of the pathophysiology of TBI but also provides a new potential target for the clinical prevention and treatment of post-traumatic white matter damage.