Cell Communication and Signaling最新文献

While α-ketoglutarate (α-KG) has traditionally been viewed as an anti-inflammatory metabolite, we uncover its paradoxical role in driving pathological inflammation during sepsis. This study reveals that α-KG, a tricarboxylic acid cycle (TCA) intermediate elevated in septic patients, drives inflammatory macrophage death through absent in melanoma 2 (AIM2) -PANoptosome activation. Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection. Mechanistically, α-KG enhances the dioxygenase activity of Ten-eleven translocation 2 (TET2), promoting its binding to the AIM2 promoter, reducing methylation, and increasing AIM2 expression, thereby triggering PANoptosome assembly. The pathophysiological relevance of this axis was confirmed by attenuated inflammation following either TET inhibition (dimethyloxallyl glycine, DMOG) or AIM2 deletion. These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality. Placental dysfunction drives the onset of the condition through inadequate spiral artery remodeling and ischemia-hypoxia, triggering endothelial cell injury mediated by small extracellular vesicles (sEVs), which can increase long-term cardiovascular risk in both mothers and offspring. However, the mechanisms underlying this process remain unclear and unpredictable. Although placental sEVs carry dysfunctional miRNAs associated with endothelial injury, traditional methods of separation from plasma/explantations are subject to contamination and physiological irrelevance. Tissue-derived sEVs extracted by enzymatic digestion have higher fidelity but remain unexplored in the placenta and PE. PTPN14 (a tyrosine phosphatase regulating YAP1 nuclear exclusion) also inhibits endothelial function, but its role in PE remains unclear.

Method: We first established a rigorous pipeline based on combined enzymatic digestion to isolate high-purity, high-yield human placental tissue-derived sEVs (p-tsEV). A three-level exploration strategy was uniquely employed, combining sequencing and integrative analyses across p-tsEV, maternal circulating sEVs, and primary fetal umbilical endothelial cells (HUVECs). Mechanistic studies utilized human placenta tissue and primary HUVECs treated with p-tsEV, miRNA mimic/inhibitor-sEVs. We performed dual-luciferase reporter assays, cell function tests, and ROC analysis.

Results: PE p-tsEV significantly induced primary HUVECs injury. miR-2110 was the most reduced miRNA in PE p-tsEV and was validated in maternal plasma sEVs (P < 0.0001). Mechanistically, low levels of miR-2110 in PE decreased the direct binding inhibition of PTPN14, increased PTPN14 expression and inhibited YAP1 activation, down-regulated key molecules such as VEGFA and CD31, thereby affecting endothelial cell function. Supplementation with miR-2110-sEVs improves endothelial cell injury, while overexpression of PTPN14 reverses this effect. Additionally, reduced plasma sEVs miR-2110 levels at 16 weeks of gestation demonstrated excellent predictive efficacy for PE (AUC = 0.85).

Conclusion: We first established the role of the miR-2110/PTPN14/YAP1 pathway regulatory network in PE endothelial cell injury. This mechanism links placental ischemia with endothelial cell injury and long-term cardiovascular risks in both mother and fetus. Our study provides a comprehensive understanding of the sEVs-mediated placenta-endothelium communication axis in PE, and miR-2110 serves as both a mechanistic mediator and an early diagnostic biomarker, offering new insights for targeted interventions and improving adverse outcomes.

Background: Kynurenine, a byproduct of tryptophan breakdown, is linked to immune suppression during cancer development. This study explores the involvement of the amino acid transporter solute carrier family 1 member 5 (SLC1A5) in kynurenine-mediated T cell exhaustion in LUAD and delves into its functional mechanism.

Methods: RNA-sequencing analysis was employed to identify transcriptome differences between T progenitor and terminal exhausted T cells (TPEX vs. TEX). The SLC1A5 expression was detected in T cells following L-kynurenine (L-ky) treatment. Mouse LUAD cells LLC were implanted into wild-type (WT), SLC1A5 knockout (SLC1A5^-/-), SLC1A5^flox/flox (SLC1A5^fl/fl), or CD8⁺ T cell-specific SLC1A5 conditional knockout (SLC1A5^cko) mice, followed by L-ky treatment, to examine the effect of SLC1A5^cko on L-ky-mediated tumorigenesis and T cell exhaustion. Interacting proteins of AHR, a core transcription factor in the kynurenine pathway, were explored by liquid chromatography/mass spectrometry and bioinformatics.

Results: SLC1A5 is upregulated in TEX, and its expression in CD8⁺ T cells was increased by L-ky treatment dose-dependently. The tumorigenic activity of LLC cells, under L-ky treatment stimulation, was suppressed in both SLC1A5^-/- and SLC1A5^cko mice, accompanied by increased T cell activity within tumors. CD8⁺ T cells extracted from SLC1A5^cko mice also showed reduced L-ky uptake and increased cytotoxicity in vitro. Mechanistically, AHR recruits the chromatin modifying enzyme FANCD2 to enhance SLC1A5 expression, promoting chromatin accessibility in T cells and cell exhaustion.

Conclusion: This study suggests that SLC1A5 is upregulated in TEX, which modulates kynurenine metabolism and induces T cell exhaustion through the AHR-FANCD2 axis-mediated chromatin remodeling.

Fibrosis, a pathological process defined by excessive extracellular matrix (ECM) accumulation, contributes significantly to chronic organ failure worldwide. The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family proteins are secreted, multi-domain matrix-associated zinc metalloendopeptidases, which have emerged as key regulators of fibrotic pathogenesis. While the ADAMTS proteins are well known for their ability to cleave ECM components such as collagens, proteoglycans, fibronectin, and fibrillins, their roles in fibrosis extend beyond conventional ECM modulators. Through precise proteolytic modification of these ECM substrates, ADAMTS members actively orchestrate upstream and core mechanisms driving fibrosis, notably TGF-β activation and fibroblast phenotype switching. Recent studies have uncovered tissue- and substrate-specific roles of individual ADAMTS members, highlighting their dual regulatory effects in fibrotic diseases and opening avenues for targeted therapeutic strategies. Despite promising preclinical results, translating ADAMTS-targeting therapies into clinical applications for fibrosis remains challenging due to their functional duality, substrate redundancy, and poorly characterized spatiotemporal specificity. This review comprehensively summarizes the proteolytic mechanisms of ADAMTS proteases toward ECM substrates, their multifaceted roles in fibrogenesis, and discusses their translational potential as therapeutic targets.

Background: Fibrosis, a hallmark of multiple chronic diseases, is regulated by transforming growth factor beta (TGF-β)-mediated PI3K-AKT signaling. Phospholipase C-related catalytically inactive protein (PRIP), also known as phospholipase C-like protein (PLCL) in humans, acts as a negative regulator of PI3K-AKT signaling. However, the role of PRIP/PLCL in fibrotic remodeling and its underlying molecular mechanisms remain unclear. Therefore, we investigated the involvement of PRIP/PLCL in fibrogenesis.

Methods: Bioinformatics analyses were performed to determine the relationship between PRIP/PLCL and fibrosis, as well as its involvement in fibrotic signaling pathways. For in vivo experiments, we developed a mouse fibrosis model using male wild-type (WT) and Prip- knockout (KO) mice treated with angiotensin II (Ang II) to evaluate fibrogenesis in the kidney and heart. For in vitro experiments, we treated mouse embryonic fibroblasts (MEFs) from WT and Prip-KO mice with TGF-β1 (5 ng/ml) to verify PRIP/PLCL-modulated signaling in fibrosis using qPCR and western blotting.

Results: Bioinformatics analyses revealed that PRIP/PLCL expression was significantly downregulated in fibrotic tissues and negatively correlated with the severity of renal fibrosis. Prip-KO mice exhibited accelerated fibrogenesis in the kidneys and heart following Ang II treatment. Consistently, PRIP deficiency exacerbated TGF-β1-induced fibroblast activation in MEFs. Gene set enrichment analysis of genes ranked by their correlation with PLCL expression revealed significant negative enrichment of the PI3K-AKT and Hippo signaling pathways. Accordingly, loss of PRIP enhanced AKT activation, promoted MST2 phosphorylation at Thr117, and facilitated the nuclear translocation of yes-associated protein (YAP), a core effector of the Hippo pathway and driver of fibrogenesis, leading to increased YAP-dependent profibrotic activity in TGF-β1-stimulated Prip-knockout MEFs.

Conclusion: PRIP/PLCL deficiency mediates YAP activation via the PI3K-AKT-MST2 axis, thereby accelerating fibroblast activation and organ fibrotic remodeling. Collectively, PRIP/PLCL acts as a novel anti-fibrotic factor, and restoring its activity could be an effective therapeutic approach for treating fibrotic diseases.