NF-κB x TREM1

Hypothermia can cause acute lung injury (ALI). The pathogenetic mechanism of hypothermic ALI involves various proteins. Cold‐inducible RNA‐binding protein (CIRP) is secreted by macrophages or damaged cells and enhances the inflammatory response, resulting in tissue and organ damage. However, it is unclear whether CIRP participates in the development of hypothermic ALI; moreover, the expression pattern of CIRP and its mechanism of action in hypothermic ALI remain unelucidated. To address this issue, we established a stable, long‐term seawater immersion‐induced hypothermic ALI rat model. CIRP expression in the rat lung tissue was downregulated by adeno‐associated virus (AAV) to determine the correlation between the expression of CIRP as well as its related signaling pathway proteins Nuclear factor‐κB (NF‐κB) and Triggering Receptor Expressed on Myeloid Cells‐1 (TREM‐1)and lung injury in a low‐temperature ALI model. A long‐term, seawater immersion‐induced hypothermic ALI rat model was established by immersing the rats in seawater at 18°C for 24 h. As the seawater immersion time increased, the intensity of ALI worsened. CIRP levels in the lung tissue and serum of rats with hypothermic ALI significantly increased in a time‐dependent manner; the levels gradually increased within 24 h and were positively correlated with the expression of inflammatory factors. CIRP knockdown in the rat lung tissue by using AAV significantly decreased the lung coefficient and injury score, reduced the levels of inflammatory factors, and attenuated the expression levels of TREM‐1 and NF‐κB. This finding suggests that CIRP exacerbates the inflammatory response in hypothermic ALI through TREM‐1 and NF‐κB‐related signaling pathways. The present study revealed that CIRP expression increased in the lung tissue and serum of rats with hypothermic ALI in a time‐dependent manner and showed a positive correlation with inflammatory factor release. Knockdown of CIRP expression in the rat lung tissue might reduce inflammation and alleviate lung injury by inhibiting TREM‐1 and NF‐κB signaling pathway proteins.

Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. Methods: We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating in vivo multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4^-/-, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. Results: Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. Conclusions: These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.

The pathophysiology of cognitive impairment has recently focused on 1,2-Diacetylbenzene (DAB), B vitamins, tau hyperphosphorylation, and neuroinflammation. While past evidence shows that vitamin B6 influences the immune system, the molecular processes behind DAB-induced neuroinflammation and cognitive impairment remain largely unknown. This study aimed to assess the protective roles of vitamin B6 against DAB-induced toxicity in BV2 microglial and SH-SY5Y cells.

In vitro approaches included Western blot, qRT-PCR, cell viability assays, immunocytochemistry, reactive oxygen species, and nitrite assays. For in silico analysis, we utilized Metascape, Cytoscape, MIENTURNET, and molecular docking.

Vitamin B6 suppressed the TLR4/NF-κB pathway and the TREM-1/DAP12/NLRP3/caspase-1/IL1B pathway in DAB-activated BV2 cells. Additionally, it reduced reactive oxygen species and nitric oxide levels while increasing Nrf2 and IL10 production. In SH-SY5Y cells, vitamin B6 inhibited GSK-3β Tyr216, tau hyperphosphorylation, and β-amyloid production. The in silico analysis identified 'positive regulation of NF-κB transcription factor activity,' 'regulation of IL-6 production,' and 'positive regulation of adaptive immune response' as key molecular mechanisms linked with DAB-induced cognitive impairment and targeted by vitamin B6. Core genes, miRNAs, and transcription factors included IL1β, IL6, IL10, TNF, hsa-miR-155-5p, hsa-miR-203a-3p, hsa-miR-106a-5p, hsa-miR-26a-5p, CEBPB, and PXR.

Our findings indicate that vitamin B6 may protect against DAB-induced cognitive impairment by attenuating key inflammatory pathways, reducing oxidative stress, and inhibiting tau hyperphosphorylation, β-amyloid production, and GSK-3β Tyr216 phosphorylation. This highlights its potential as a therapeutic agent for cognitive impairment.