Biology subjects

Alazawi, W.

Publications and source records attributed to Alazawi, W..

3 recordsLinked to original sources

bioRxiv2026

Mapping vascular plasticity in liver fibrogenesis identifies novel fibrosis-associated endothelial cells in early-stage liver disease

Vascular plasticity is a crucial biological asset enabling our bodies to rapidly adapt to infections and acute inflammation. However, repeated insult during chronic disease can result in these vascular adaptations becoming irreversible, thereby driving disease progression and fibrosis. This study aimed to understand if phenotypic changes in endothelial cell (EC) identity could be indicative of progressive fibrosis and thereby offer new diagnostic and therapeutic opportunities for patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Previous research has documented that a significant shift in EC transcriptomic signature occurs during liver fibrosis in both pre-clinical models and patients. However, the protein expression profile, phenotype and functional role of these new EC subpopulations that are induced during fibrogenesis is unclear. In this study, we integrate high-resolution imaging, proteomic and transcriptomic analysis which collectively highlight a central role for endothelial-to-mesenchymal transition (EndMT)-induced EC plasticity in the derivation of fibrosis-associated EC (FAEC). We demonstrate that: 1) full spectrum flow cytometry can provide new opportunities to categorize and phenotype EC subpopulations, 2) two distinct EndMT-derived FAEC subpopulations expand during fibrogenesis; THY1.2+ICAM1+ and TAGLN+MCAM+ EC that display unique immunomodulatory and metabolic phenotypes, 3) TAGLN+ FAEC are a conserved, pro-fibrotic cell type arising at early stages of MASLD, and 4) increased hepatic expression of TAGLN is significantly associated with detrimental patient outcomes at all stages of liver disease. This study will pave the way for the development of FAEC-specific diagnostic and therapeutic approaches to tackle progressive fibrotic disease. One Sentence SummaryPhenotyping fibrosis-associated endothelial cells reveals pro-fibrotic and immunomodulatory subpopulations at early stages of liver disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/710459v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@dc91fforg.highwire.dtl.DTLVardef@f526d9org.highwire.dtl.DTLVardef@c9783borg.highwire.dtl.DTLVardef@f469e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

TLR5 drives metabolic dysfunction-associated steatohepatitis through lipid- and flagellin-induced hepatocyte injury signalling

Liver fibrosis is a strong predictor of clinical outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Fibrosis is a consequence of persistent liver cell injury and inflammation in which Toll-like receptors (TLRs) play a key initiating role. Here we test the hypothesis that TLR5 is involved in the development of MASH and fibrosis using a combination of clinical data from multiple independent patient cohorts, single cell liver transcriptomics and human in vitro and ex vivo models. Hepatic TLR5 expression, but not TLR2 or TLR4, is associated with liver fibrosis and mortality. Plasma levels of TLR5s cognate ligand flagellin are increased in MASH with advanced fibrosis and fall with liver disease improvement. Mechanistically, we identify two parallel TLR5-mediated routes to hepatocyte injury: one elicited by flagellin and the other indirectly by lipid injury. Furthermore, hepatocyte TLR5 inhibition abrogates paracrine activation of hepatic stellate cells to suppress collagen production. This is also seen ex vivo in patient-derived precision-cut liver slices where TLR5 inhibition significantly reduces lipid-induced collagen deposition. These findings reveal a new role for TLR5 signalling, specifically in the development of advanced MASH fibrosis and may offer a novel disease-specific therapeutic approach.

molecular biology↗

bioRxiv2019

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-{kappa}B-mediated sepsis. However its role in sterile inflammation is unknown. We hypothesised that Stat2 determines severity of non-infective inflammation in the pancreas.\n\nWild type (WT) and Stat2-/- mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells.\n\nStat2-/- mice were protected from cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels including TNF and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNF improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre) reduced pancreatic TNF expression, but not histological injury or serum amylase. WT/Stat2-/- bone-marrow chimera were protected from pancreatitis irrespective of host or recipient genotype.\n\nStat2 loss results in disrupted signalling in pancreatitis, upstream of NF-{kappa}B in non-acinar and/or bone marrow derived cells.

immunology↗