Biology subjects

Lu, W.-Y.

Publications and source records attributed to Lu, W.-Y..

4 recordsLinked to original sources

bioRxiv2025

Regulatory T cell stability determines the efficiency of bile duct regeneration during cholangitis.

Background and AimsCholangiopathies such as Primary Sclerosing Cholangitis (PSC) cause damage to the bile ducts and fibrosis with no effective cure. A reduction and impairment in the function of regulatory T cells (Tregs) occurs in PSC. Yet, it is currently unknown what consequence this has on bile duct regeneration. We investigate whether Tregs regulate bile duct regeneration and the dynamics of Tregs turnover during bile duct injury. Approach and ResultsWe used the transgenic Foxp3GFPDTR model to mimic reduced Tregs infiltration to the liver during bile duct injury and showed that reduced intrahepatic Tregs limits bile duct regeneration. Fate mapping of Tregs (Foxp3CreERTAi14) showed that Tregs acquire a pro-inflammatory phenotype within the inflammatory microenvironment, even after IL2 mediated Tregs expansion. Ox40L expression correlates with fibrosis in PSC patients. In the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet mouse model of experimental cholangiopathy, combining IL2-complex administration and blocking Ox40L decreases periportal fibrosis level, increases Treg number and reduces the pro-inflammatory phenotype of Tregs. ConclusionsThese results indicate that Tregs mediate cholangiocyte response to biliary injury, and Tregs downregulate Foxp3 and acquire an inflammatory phenotype in an inflammatory microenvironment. Enhancing Treg numbers through IL2 complex administration and blocking Ox40 signalling simultaneously suppress the inflammatory phenotype of Tregs and reduces bile duct damage and fibrosis.

immunology↗

bioRxiv2023

Utilising an in silico model to predict outcomes in senescence-driven acute liver injury

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet demand and transplant recipients require lifelong immunosuppression. The identification of alternative treatments, e.g. cell therapies, able to tip resolution of injury from inflammation to regeneration requires an understanding of the host response to the degree of injury. We adopt a combined in vivo-in silico approach and develop a mathematical model of acute liver disease able to predict the host response to injury. We utilise the Mdm2fl/fl mouse model together with a single Cre induction through intravenous injection of the hepatotropic Adeno-associated Virus Serotype 8 Cre (AAV8.Cre) to model acute liver injury. We derive a complementary ordinary differential equation model to capture the dynamics of the key cell players in the injury response together with the extracellular matrix. We show that the mathematical model is able to predict the host response to moderate injury via qualitative comparison of the model predictions with the experimental data. We then use the model to predict the host response to mild and severe injury, and test these predictions in vivo, obtaining good qualitative agreement.

cell biology↗

bioRxiv2020

Chronic hM3Dq signaling in microglia ameliorates neuroinflammation in male mice

Microglia express muscarinic G protein-coupled receptors (GPCRs) that sense cholinergic activity and are activated by acetylcholine to potentially regulate microglial functions. Knowledge about how distinct types of muscarinic GPCR signaling regulate microglia function in vitro and in vivo is still poor, partly due to the fact that some of these receptors are also present in astrocytes and neurons. We generated mice expressing the hM3Dq Designer Receptor Exclusively Activated by Designer Drugs (DREADD) selectively in microglia to investigate the role of muscarinic M3Gq-linked signaling. We show that activation of hM3Dq using clozapine N-oxide (CNO) elevated intracellular calcium levels and increased phagocytosis of FluoSpheres in vitro. Acute treatment with CNO in vivo did not affect male mouse behavior, however chronic CNO treatment decreased sickness behavior triggered by lipopolysaccharide (LPS) treatment. Interestingly, whereas acute treatment with CNO increased synthesis of cytokine mRNA, chronic treatment attenuated LPS-induced cytokine mRNA changes in the brain, likely explaining the improvement in sickness behavior by chronic hM3Dq activation. No effect of CNO was observed in DREADD-negative mice. These results suggest that chronic activation of M3 muscarinic receptors (the hM3Dq progenitor) in microglia, and potentially other Gq-coupled GPCRs, preconditions microglia to decrease their response to further immunological challenges. Our results indicate that hM3Dq can be a useful tool to modulate neuroinflammation and study microglial immunological memory in vivo, which may be applicable for manipulations of neuroinflammation in neurodegenerative and psychiatric diseases. HighlightsO_LIMicroglial function was manipulated by specific activation of hM3Dq signaling. C_LIO_LIChronic hM3Dq activation prevented LPS-induced sickness behavior in mice. C_LIO_LIMicroglial hM3Dq signaling modulated expression of pro-inflammatory cytokines. C_LI

neuroscience↗

bioRxiv2018

S-Nitrosylation of STIM1 by neuronal nitric oxide synthase inhibits store-operated Ca2+ entry

Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule-1 (STIM1) and Orai1 represents a major route of Ca2+ entry in mammalian cells and is initiated by STIM1 oligomerization in the endoplasmic or sarcoplasmic reticulum (ER/SR). However, the effects of nitric oxide (NO) on STIM1 function are unknown. Neuronal NO synthase (nNOS) is located in the SR of cardiomyocytes. Here, we show that STIM1 is susceptible to S-nitrosylation. nNOS deficiency or inhibition enhanced Ca2+ release-activated Ca2+ channel current (ICRAC) and SOCE in cardiomyocytes. Consistently, NO donor S-nitrosoglutathione (GSNO) inhibited STIM1 puncta formation and ICRAC in HEK293 cells, but this effect was absent in cells expressing the Cys49Ser/Cys56Ser STIM1 double mutant. Furthermore, NO donors caused Cys49 and Cys56-specific structural changes associated with reduced protein backbone mobility, increased thermal stability and suppressed Ca2+-depletion-dependent oligomerization of the luminal Ca2+-sensing region of STIM1. Collectively, our data show that S-nitrosylation of STIM1 suppresses oligomerization via enhanced luminal domain stability and rigidity, and inhibits SOCE in cardiomyocytes.

physiology↗