Cell Communication and Signaling最新文献

In mast cells, endo- and exocytotic pathways are central to the (patho)physiological release of pro-inflammatory mediators, linking intracellular signaling with immune communication. Proton-activated chloride (PAC) channel mediates acid-sensitive outwardly rectifying anion channel (ASOR/PAORAC) currents, however, its physiological functions are poorly understood.Using electrophysiology, live-cell imaging, electron microscopy, and functional assays, we investigate the role of PAC in human mast cells.We detected ASOR/PAORAC in primary human mast cells and mast cell lines and demonstrated its essential role in vesicular signaling. PAC knockout reduced vesicular pH, increased endocytosis, decreased exocytosis, and disrupted endolysosomal homeostasis. Upon activation of exocytosis, the lack of PAC reduced CD107a (LAMP-1) surface expression. PAC-deficient cells also displayed increased colocalization of lysosomes and mitochondria, elevated ROS levels, and the appearance of C-shaped mitochondria, suggesting that PAC regulates inter-organelle stress signaling. Functionally, PAC knockout impaired mitochondrial respiration, linking ion channel activity to mast cell metabolic adaptation.These findings establish PAC as a key regulator of endo- and exocytosis-dependent signaling and lysosomal-mitochondrial stress response in human mast cells, highlighting its physiological relevance and potential as a therapeutic target in mast cell-associated disorders.

Gut barrier dysfunction is a key feature of acute liver injury (ALI) and leads to systemic immune responses (SIRS). Our previous studies have demonstrated that knockout of osteopontin (OPN) modulates antimicrobial peptide expression and reduces intestinal flora, thereby ameliorating sepsis. In this study, we employed an acetaminophen (APAP)-induced hepatotoxicity model, the leading cause of acute liver failure (ALF) worldwide, to investigate the role of intestinal epithelial-derived OPN in gut barrier integrity during ALF. We found that intestinal epithelial-specific OPN knockout mice (Opn^△IEC) exhibited significant protection against APAP-induced liver injury and reduced gut barrier leakage. Fecal transplantation experiments revealed that mice receiving feces from Opn^△IEC mice showed increased resistance to APAP-induced liver injury and enhanced immune defense. Mechanistically, transcriptome analysis of the gut barrier indicated that OPN exacerbated gut barrier damage by inhibiting gut self-renewal via the JAK3/STAT4 signaling pathway. Epithelial-derived OPN may play a critical role in compromising gut barrier integrity and may be a target for suppressing inflammation and ameliorating ALI.

The intricate relationship between microbiota and breast cancer presents an additional risk factor that can have a profound impact on disease progression. Focusing on dysbiosis, our metagenomic analysis shows overabundance of an oral pathogenic microbe F. nucleatum and co-habitation of associated biofilm forming oral microbes in cancerous breast. Mammary gland colonization with F. nucleatum results in the development of metaplastic lesions accompanied with inflammation, DNA damage and hyper-proliferation in healthy mice. Exhibiting the impact of circulating F. nucleatum introduced via hematogenous route, breast tumor bearing mice show accelerated tumor growth and metastatic progression. Increased proliferation, migration, self-renewal and chemoresistance in breast cancer cells as well as non-tumorigenic breast epithelial cells bearing pathogenic BRCA1 mutation is observed upon F. nucleatum exposure which is internalized by the cells in a Gal-GalNAc dependent manner. Of interest, cells harboring BRCA1 mutations exhibit greater cell surface accumulation of Gal-GalNAc sugar residue. This work sheds light on the oncogenic impact of a pro-carcinogenic oral bacterium, F. nucleatum, on normal mammary epithelium and breast cancer, implicates the impairment of DNA damage and repair pathways as its functional mediators, and proposes the concept of increased vulnerability of BRCA1 mutant breast cancer cells owing to their preferential internalization of F. nucleatum.