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.

Trends in Adherence to Recommended Physical Activity and Its Association with Mortality and Disease Progression among US Adults with Chronic Kidney Disease.

INTRODUCTION: This study aimed to examine the trends in adherence to the Physical Activity Guidelines (PAG) for aerobic activity and sedentary time and their effects on mortality and disease progression among US adults with chronic kidney disease (CKD). METHODS: We studied individuals from the National Health and Nutrition Examination Survey 2007-08 to 2017-18 with a mortality file in 2015. Multivariate regression models were used to evaluate the association between adherence to PAG and sedentary time with mortality, estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio. RESULTS: For the CKD population, adherence rate increased from 48.2% in 2007-08 to 55.0% in 2017-18, and sedentary time peaked in 2013-14 (7.5 h/day) and then decreased afterward. There was no difference in the trends across the non-CKD and CKD population. For the CKD population, adherence to the PAG was significantly associated with all-cause mortality (HR, 0.49; 95% CI: 0.38-0.63), malignant neoplasm mortality (HR, 0.30; 95% CI: 0.17-0.52), and albumin-creatinine ratio (OR, -0.27; 95% CI: -0.39 to -0.15). Sedentary time was significantly associated with all-cause mortality (HR, 1.12; 95% CI: 1.08-1.15), heart disease mortality (HR, 1.13; 95% CI: 1.08-1.19), and eGFR (OR, -0.49; 95% CI: -0.72 to -0.26). CONCLUSIONS: Favorable trends were observed in adherence to the PAG and sedentary time. Adherence to the PAG and reduction in sedentary time reduced all-cause and cause-specific mortality and prevented disease progression differently. Efforts are needed to decrease sedentary time rather than adhering to the PAG for aerobic activity alone.

Screening of Codonopsis radix Polysaccharides with Different Molecular Weights and Evaluation of Their Immunomodulatory Activity In Vitro and In Vivo.

Polysaccharide is one of the main components of Codonopsis radix (CR) and has good immune activity. However, the immune activity of CR polysaccharides with different molecular weights has not been systematically screened. In this study, the polysaccharides of CR from Pingshun of Shanxi Province (PSDSs) were first divided into two groups using ultrafiltration: 3.3 kDa (PSDSs-1) and more than 2000 kDa (PSDSs-2). The immunomodulatory effects of PSDSs with different molecular weights were evaluated in vitro and in vivo. In vitro experimental results showed that compared with Lipopolysaccharide-induced macrophages, PSDSs-1 increased TNF-α and IL-6 levels and decreased IL-10. Meanwhile, PSDSs-2 showed the opposite effect, indicating the difference in pro- and anti-inflammatory activities of PSDSs with different molecular weights. The immunosuppressive model of cyclophosphamide proved that PSDSs have immune-promoting function, with PSDSs-1 exhibiting a better effect than PSDSs-2. In vitro and in vivo experiments illustrated the complexity of PSDS immunomodulation. Further research on the functions of PSDs with different molecular weights is needed to lay a foundation for their classification and application.

NETs Lead to Sympathetic Hyperactivity After Traumatic Brain Injury Through the LL37-Hippo/MST1 Pathway.

Background: Paroxysmal sympathetic hyperactivity (PSH) is one of the important reasons for the high mortality and morbidity of traumatic brain injury (TBI). We aim to explore the role of the neutrophil extracellular traps (NETs) in the pathogenesis of sympathetic hyperexcitability after TBI and the underlying mechanisms, providing evidence for clinical treatment. Methods: Enzyme-linked immunosorbent assay was used to assess the plasma metanephrine and normetanephrine levels which represented the variation of the sympathetic system after TBI with rat diffuse axonal injury (DAI) model. NETs in the paraventricular nucleus (PVN) and circulating blood were examined using immunofluorescence and flow cytometry. Neutrophils-microglia co-culture system was established to further explore the effect of NETs on PSH and its mechanisms. Results: After TBI, metanephrine and normetanephrine levels began to increase at 9 h and peaked at 72 h. After the injury, the level of NETs kept increasing at 24 and 72 h in the PVN. A positive correlation was found between the concentration of the PVN NETs and blood catecholamine. Flow cytometry of peripheral blood cells revealed that NETs level in the injury group was higher than that in the control group. Immunofluorescence results confirmed the presence of NETs in the PVN after TBI. The positive result of immunoprecipitation suggested a correlation effect between LL37 and P2 × 7. Peptidyl arginine deiminase-4 (PAD4) inhibitor could inhibit the expression levels of MST1, YAP, and IL-1ß. The hippo/MST1 pathway inhibitor could inhibit the expression levels of YAP and IL-1ß. Conclusion: NETs formation in the PVN might be associated with sympathetic hyperactivity after TBI, which might relate to the activation of microglia cells and increased secretion of IL-1ß via the hippo/MST1 pathway.

The association of traumatic brain injury, gut microbiota and the corresponding metabolites in mice.

BACKGROUND: Traumatic Brain Injury (TBI) present a significant burden to global health. Close association and mutual regulation exist between the brain and gut microbiota. In addition, metabolites may play an important role as intermediary mediators of the brain and gut microbiota. Consequently, the study sought to investigate the alterations in gut microbiota and metabolites after TBI and conducted a comprehensive analysis of the correlation between gut microbiota and metabolites after TBI in mice. METHODS: Changes in intestinal microbiota and metabolites in mice after moderate or severe traumatic brain injury were detected through 16S rDNA sequencing and the non-target LC-MS technology. Additionally, Pearson correlation analysis was used to explore the association between the microbiota and metabolites. RESULTS: TBI was able to change the composition of intestinal microbiota, resulting to a decrease in microbial diversity in the intestinal tract (sham vs sTBI: 8.35 ± 0.12 vs 7.71 ± 0.5, p < 0.01; sTBI vs mTBI: 7.71 ± 0.5 vs 8.25 ± 0.34, p < 0.05). The results also showed that TBI could change the types and abundance of metabolites (723 in mTBI and sham groups; 1221 in sTBI and sham groups; 324 in mTBI and sTBI groups). Moreover, some of the altered gut metabolites were significantly correlated with part of the altered gut microbes after TBI. CONCLUSIONS: TBI significantly changed intestinal microbiota as well as metabolites. Some of the altered microbiota and metabolites had a significant association. The results from this study provide information that paves way for future studies utilizing the brain gut axis theory in the diagnosis and treatment of TBI.