CD36 deletion prevents white matter injury by modulating microglia polarization through the Traf5-MAPK signal pathway.

BACKGROUND: White matter injury (WMI) represents a significant etiological factor contributing to neurological impairment subsequent to Traumatic Brain Injury (TBI). CD36 receptors are recognized as pivotal participants in the pathogenesis of neurological disorders, including stroke and spinal cord injury. Furthermore, dynamic fluctuations in the phenotypic polarization of microglial cells have been intimately associated with the regenerative processes within the injured tissue following TBI. Nevertheless, there is a paucity of research addressing the impact of CD36 receptors on WMI and microglial polarization. This investigation aims to elucidate the functional role and mechanistic underpinnings of CD36 in modulating microglial polarization and WMI following TBI. METHODS: TBI models were induced in murine subjects via controlled cortical impact (CCI). The spatiotemporal patterns of CD36 expression were examined through quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescence staining. The extent of white matter injury was assessed via transmission electron microscopy, Luxol Fast Blue (LFB) staining, and immunofluorescence staining. Transcriptome sequencing was employed to dissect the molecular mechanisms underlying CD36 down-regulation and its influence on white matter damage. Microglial polarization status was ascertained using qPCR, Western blot analysis, and immunofluorescence staining. In vitro, a Transwell co-culture system was employed to investigate the impact of CD36-dependent microglial polarization on oligodendrocytes subjected to oxygen-glucose deprivation (OGD). RESULTS: Western blot and qPCR analyses revealed that CD36 expression reached its zenith at 7 days post-TBI and remained sustained at this level thereafter. Immunofluorescence staining exhibited robust CD36 expression in astrocytes and microglia following TBI. Genetic deletion of CD36 ameliorated TBI-induced white matter injury, as evidenced by a reduced SMI-32/MBP ratio and G-ratio. Transcriptome sequencing unveiled differentially expressed genes enriched in processes linked to microglial activation, regulation of neuroinflammation, and the TNF signaling pathway. Additionally, bioinformatics analysis pinpointed the Traf5-p38 axis as a critical signaling pathway. In vivo and in vitro experiments indicated that inhibition of the CD36-Traf5-MAPK axis curtailed microglial polarization toward the pro-inflammatory phenotype. In a Transwell co-culture system, BV2 cells treated with LPS + IFN-γ exacerbated the damage of post-OGD oligodendrocytes, which could be rectified through CD36 knockdown in BV2 cells. CONCLUSIONS: This study illuminates that the suppression of CD36 mitigates WMI by constraining microglial polarization towards the pro-inflammatory phenotype through the down-regulation of the Traf5-MAPK signaling pathway. Our findings present a potential therapeutic strategy for averting neuroinflammatory responses and ensuing WMI damage resulting from TBI.

Neutrophil extracellular traps facilitate sympathetic hyperactivity by polarizing microglia toward M1 phenotype after traumatic brain injury.

Traumatic brain injury (TBI), particularly diffuse axonal injury (DAI), often results in sympathetic hyperactivity, which can exacerbate the prognosis of TBI patients. A key component of this process is the role of neutrophils in causing neuroinflammation after TBI by forming neutrophil extracellular traps (NETs), but the connection between NETs and sympathetic excitation following TBI remains unclear. Utilizing a DAI rat model, the current investigation examined the role of NETs and the HMGB1/JNK/AP1 signaling pathway in this process. The findings revealed that sympathetic excitability intensifies and peaks 3 days post-injury, a pattern mirrored by the activation of microglia, and the escalated NETs and HMGB1 levels. Subsequent in vitro exploration validated that HMGB1 fosters microglial activation via the JNK/AP1 pathway. Moreover, in vivo experimentation revealed that the application of anti-HMGB1 and AP1 inhibitors can mitigate microglial M1 polarization post-DAI, effectively curtailing sympathetic hyperactivity. Therefore, this research elucidates that post-TBI, NETs within the PVN may precipitate sympathetic hyperactivity by stimulating M1 microglial polarization through the HMGB1/JNK/AP1 pathway.

An exhaustive analysis of post-traumatic brain injury dementia using bibliometric methodologies.

Background: It is widely accepted that traumatic brain injury (TBI) increases the risk of developing long-term dementia, although some controversies surrounding this topic exist. Annually, approximately 69 million individuals suffer from TBI all around the world. Such a large population of TBI patients could lead to a future surge in the number of dementia patients. Due to the potentially severe consequences of TBI, various research projects on post-TBI dementia have emerged worldwide. Therefore, it is essential to comprehend the current status and development of post-TBI dementia for future research. Objective: The purpose of the study was to provide an overview of the field and identify hotspots, research frontiers, and future research trends for post-TBI dementia. Methods: Articles related to post-TBI dementia were retrieved from the Web of Science Core Collection for the period between 2007 and 2022, and analyzing them based on factors such as citations, authors, institutions, countries, journals, keywords, and references. Data analysis and visualization were conducted using VOSviewer, CiteSpace, and an online bibliometric platform (https://bibliometric.com). Results: From 2007 to 2022, we obtained a total of 727 articles from 3,780 authors and 1,126 institutions across 52 countries, published in 262 journals. These articles received a total of 29,353 citations, citing 25,713 references from 3,921 journals. Over the last 15 years, there has been a significant upward trend in both publications and citations. The most productive country was the United States, the most productive institution was Boston University, and the most productive author was McKee AC. Journal of Neurotrauma has been identified as the periodical with the greatest number of publications. Three clusters were identified through cluster analysis of keywords. A burst in the use of the term "outcome" in 2019 is indicative of a future research hotspot. The timeline view of references showed 14 clusters, of which the first 4 clusters collected the majority of papers. The first 4 clusters were "chronic traumatic encephalopathy," "age of onset," "tauopathy," and "cognitive decline," respectively, suggesting some areas of interest in the field. Conclusion: The subject of post-TBI dementia has raised much interest from scientists. Notably, America is at the forefront of research in this area. Further collaborative research between different countries is imperative. Two topical issues in this field are "The association between TBI and dementia-related alterations" and "chronic traumatic encephalopathy (CTE)." Studies on clinical manifestation, therapy, pathology, and pathogenic mechanisms are also popular in the field.

Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer.

Methyladenosine modifications are the most abundant RNA modifications, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 2'-O-methyladenosine (m6Am). As reversible epigenetic modifications, methyladenosine modifications in eukaryotic RNAs are not invariable. Drastic alterations of m6A are found in a variety of diseases, including cancers. Dynamic changes of m6A modification induced by abnormal methyltransferase, demethylases, and readers can regulate cancer progression via interfering with the splicing, localization, translation, and stability of mRNAs. Meanwhile, m6A, m1A, and m6Am modifications also exert regulatory effects on noncoding RNAs in cancer progression. In this paper, we reviewed recent findings concerning the underlying biomechanism of methyladenosine modifications in oncogenesis and metastasis and discussed the therapeutic potential of methyladenosine modifications in cancer treatments.