Pierre-Yves von der Weid’s research while affiliated with University of Calgary and other places

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Publications (87)


Rhamnogalacturonan promotes intestinal mucosal repair through increased cell migration
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January 2025

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16 Reads

AJP Gastrointestinal and Liver Physiology

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RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.


Vascular Endothelial Growth Factor C (VEGF-C) Sensitizes Lymphatic Endothelial Cells to Oxidative-Stress-Induced Apoptosis through DNA Damage and Mitochondrial Dysfunction: Implications for Lymphedema
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  • Full-text available

July 2024

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39 Reads

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1 Citation

International Journal of Molecular Sciences

Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon H2O2 treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.

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Flow-dependent regulation of rat mesenteric lymphatic vessel contractile response requires activation of endothelial TRPV4 channels

December 2023

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11 Reads

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1 Citation

Microcirculation (New York, N.Y.: 1994)

Objectives The objective of our study is to evaluate the involvement of the transient receptor potential vanilloid 4 (TRPV4) in the alteration of lymphatic pumping in response to flow and determine the signaling pathways involved. Methods We used immunofluorescence imaging and western blotting to assess TRPV4 expression in rat mesenteric lymphatic vessels. We examined inhibition of TRPV4 with HC067047, nitric oxide synthase (NOS) with L‐NNA and cyclooxygenases (COXs) with indomethacin on the contractile response of pressurized lymphatic vessels to flow changes induced by a stepwise increase in pressure gradients, and the functionality of endothelial TRPV4 channels by measuring the intracellular Ca ²⁺ response of primary lymphatic endothelial cell cultures to the selective agonist GSK1016790A. Results TRPV4 protein was expressed in both the endothelial and the smooth muscle layer of rat mesenteric lymphatics with high endothelial expression around the valve sites. When maintained under constant transmural pressure, most lymphatic vessels displayed a decrease in contraction frequency under conditions of flow and this effect was ablated through inhibition of NOS, COX or TRPV4. Conclusions Our findings demonstrate a critical role for TRPV4 in the decrease in contraction frequency induced in lymphatic vessels by increases in flow rate via the production and action of nitric oxide and dilatory prostanoids.


Not Just Fibrotic: Endothelial-derived TGFβ Maintains Contractile Function and Lymphatic Muscle Phenotype during Homeostasis

December 2023

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28 Reads

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1 Citation

AJP Cell Physiology

Cell-cell communication within the lymphatic vasculature during homeostasis is incompletely detailed. While many discoveries highlight the pathological roles of TGFβ in chronic vascular inflammation and associated fibrosis, only a small amount is known surrounding the role of TGFβ-signalling in homeostatic lymphatic function. Here, we discovered that pharmacological blockade of TGFβR1 negatively impacts rat mesenteric lymphatic vessel pumping, significantly reducing vessel contractility and surrounding lymphatic muscle coverage. We have identified mesenteric lymphatic endothelial cells themselves as a source of endogenous vascular TGFβ and that TGFβ production is significantly increased in these cells via activation of a number of functional pattern recognition receptors they express. We show a continuous supply of TGFβ is essential to maintain the contractile phenotype of neighbouring lymphatic muscle cells and support this conclusion through in vitro analysis of primary isolated lymphatic muscle cells which undergo synthetic differentiation during 2D cell culture, a phenomenon that could be effectively rescued by supplementation with recombinant TGFβ. Finally, we demonstrate that lymphatic endothelial production of TGFβ is regulated, in part, by nitric oxide in a manner we propose is essential to counteract the pathological over-production of TGFβ. Taken together, these data highlight the essential role of homeostatic TGFβ signalling in the maintenance of lymphatic vascular function and highlight possible deleterious consequences of its inhibition.



Figure 1. Characterization of the in vitro function of aptamers with Mincle affinity (A) Binding characteristics of AptMincle, and its modified counterparts, with rhMincle as determined by ELONA. (B) Graphical depiction of the modifications made to the aptamer sequences (black, original; white, modified). (C) The predicted secondary and tertiary structures and docking simulation of AptMincle CORE (purple) with Mincle (white). Box: highlighted predicted region of interaction surrounding a calcium molecule. (D) The predicted secondary and tertiary structures and docking simulation of AptMincle RND (purple) with Mincle (white). Box: highlighted predicted region of interaction surrounding a calcium molecule. Dissociation constants were calculated on GraphPad Prism 8 using a non-linear regression binding analysis with assumed one-site target parameters.
Figure 3. AptMincle DRBL suppresses DSS-induced colitis through a dose-dependent inhibition of colonic inflammation (A) Daily changes in disease activity score (DAI) over the onset of DSS-induced colitis. (B) MPO activity within colon. (C) Body weight percentage change at the end of the experiment. (D) Colon length and (E) terminal DAI measured at day 7 with relation to treatment groups with AptMincle DRBL (0.35, 1, or 3.5 mg/kg) or AptMincle RND (3.5 mg/kg). Immunoblot analysis of (F) Syk or (G) P65 phosphorylation of total colonic lysates. (H) Representative photographs of colons from mice (DSS + AptMincle DRBL is 3.5 mg/kg group only). These data are presented as the mean ± SEM and were analyzed by a repeated measures ANOVA with Tukey's post hoc test. Black asterisks indicate significance against sham group, while red asterisks indicate significance compared with DSS group: *p < 0.05, ***p < 0.001, ****p < 0.0001. Mice are a composite of 10-week-old mice, n = 4-12, with experiments performed on separate days.
Mincle-binding DNA aptamer demonstrates therapeutic potential in a model of inflammatory bowel disease

June 2022

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65 Reads

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11 Citations

Molecular Therapy — Nucleic Acids

Pattern recognition receptors such as Mincle (Clec4e) play a significant role in the regulation of inflammation. Enhanced signaling of Mincle through the release of damage-associated molecular patterns during sterile inflammation has been shown to be important in the progression and manifestation of several diseases. A limitation to Mincle-targeted therapeutics is the feasibility of human-scale antibody therapy and the lack of alternative small-molecule inhibitors. Herein, we describe a highly specific neutralizing DNA aptamer targeting Mincle and demonstrate its therapeutic potential. Our data demonstrate that AptMincle selectively binds to both human and mouse Mincle with high affinity and is able to directly target and reduce Mincle activation. AptMincle can specifically reduce trehalose-6,6-dibehenate (TDB)-induced Syk and P65 phosphorylation in vitro in a manner comparable to that of the commercially available neutralizing antibody in vitro. Moreover, a bio-stable modified aptamer, AptMincleDRBL, was successful in reducing disease activity in a dextran sodium sulfate (DSS)-induced model of ulcerative colitis in a dose- and sequence-dependent manner. The results present an alternative, highly specific DNA aptamer with antagonistic function for use in the investigation of Mincle-associated diseases. The data also show the translational potential of Mincle-targeting aptamers as a new category of biologic therapy in the treatment of inflammatory bowel disease (IBD).


A18 DEVELOPMENT OF CHRONIC ILEITIS IN THE TNFΔARE MOUSE IS ASSOCIATED WITH A LOSS OF MESENTERIC LYVE1+ MACROPHAGES

February 2022

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41 Reads

Journal of the Canadian Association of Gastroenterology

Background Crohn’s disease (CD) is a form of inflammatory bowel disease that causes transmural inflammation of any part of the gastrointestinal (GI) tract but preferentially the terminal ileum and/or the colon. This chronic inflammation is not limited to the GI tract but also affects the mesentery of inflamed regions where it induces the formation of tertiary lymphoid organs (TLOs). The homeostatic LYVE1+ macrophages (LYmΦ) have been identified in many different organs including the mesentery. They have been shown to typically align along blood vessels where they participate in the control of collagen deposition and during inflammation, regulate vascular permeability and immune cell recruitment. Here we investigate the role of the mesenteric LYmΦ in a transgenic model of CD, the TNFΔARE mouse which develops terminal ileitis over time and expresses similar mesenteric alterations (TLOs) as seen in CD. Aims To determine whether the mesenteric LYmΦ population is altered during the development of chronic inflammation in the TNFΔARE mouse and whether they participate in the development of TLOs. Methods Confocal immunofluorescent imaging of the terminal ileal mesentery of TNFΔARE mice and littermate controls were preformed to identify changes to the populations of LYmΦ during the development of chronic inflammation. Myeloperoxidase activity was used to assess terminal ileitis. Results During the initial stage of ileitis (8 weeks) LYmΦs are present across the terminal ileal mesentery in both TNFΔARE and age-matched WT littermate controls with a subpopulation aligning along the collecting lymphatic vessels of the mesentery (n=6). At 20 weeks, while the ileitis progresses, aggregates of CD45+ cells have formed within the TNFΔARE mice where LYmΦs also accumulate (n=5). At 28 weeks when the ileitis worsens, the LYmΦs are greatly reduced from the terminal ileal mesentery as well as from the CD45+ cell aggregates (n=5). WT littermate controls never develop large CD45+ cell aggregates (n=5 for each time point). Antibodies to the LYVE1 cytosolic and extracellular domains confirmed the loss of the LYVE1 receptor over receptor cleavage, however, there was no correlation of altered collagen-1 deposition within the mesentery at 28 weeks. Conclusions Here we show a spatial relationship between LYmΦs and collecting lymphatic vessels as well as a decrease in LYmΦs during the development of chronic ileitis in the TNFΔARE mouse. Whether they contribute to TLO formation, or their loss exacerbates terminal ileitis is still unknown and under current investigation. Funding Agencies CCC


Figure 2. The lactone ring structures of Lovastatin and Simvastatin are intrinsic to the statin-induced alteration of mesenteric lymphatic vessel contraction frequency, ejection fraction, and fractional pump flow. (Ai) Lovastatin vs. (Aii) Lovastatin-hydroxyacid (contraction frequency/baseline (%) concentration-response curve) (B) Calculated fractional pump flow (FPF) and (D) ejection fraction (EF) of vessels in response to concentration-dependent stimulation of statin used in A and E, respectively. (Ei) Simvastatin vs. (Eii) Simvastatin-hydroxyacid (contraction frequency/baseline (%) concentration-response curve). (Fi, ii) Calculated Fractional pump flow (FPF) and (Hi, ii) ejection fraction (EF) of vessels in response to a concentration-dependent increase in Simvastatin or Simvastatin Hydroxyacid. (C & G) Skeletal chemical structures of drugs used in panels i and ii. n = 4-12 lymphatic vessels from 4-12 different rats. Chemical structures drawn using ChemDraw.
Figure 3. Mitochondrial network fission in mesenteric lymphatic smooth muscle cells of Simvastatin-treated rats. Primary LMCs were treated in vitro with 10 μM of Lovastatin or Simvastatin for
Figure 4. Effect of Lovastatin on the contractibility of mesenteric collecting lymphatic vessels is independent of nitric oxide and/or prostaglandin synthesis. Representative traces of isolated and pressurized rat mesenteric lymphatic vessels were incubated with increasing concentrations of (Ai) Lovastatin, (Bi) LNA pre-treated vessels, or (Ci) vessels pre-treated with LNA + Indomethacin. (Aii-Cii) Plots for vessel contraction frequency displayed as a percentage of baseline, monitored for a 5 min period at each incremental concentration of Lovastatin. Raw representative traces are shown, clipped to 5 min periods. Data are presented as the percentage of baseline frequency of individual vessels. n = 5-10 individual experiments.
Figure 5. Lovastatin modulates the effect of RhoKinase inhibitor Y27637 in rat mesenteric collecting lymphatic vessels and isolated smooth muscle cells. Isolated and pressurized rat mesenteric lymphatic vessels were (Ai,Bi) baseline control, preincubated with either (Aii) 3 μM Y27637 or (Bii) 3 μM Lovastatin for 20 min before being co-incubated with (Aiii) 3 μM
Figure 6. Pro-drug form of Lovastatin inhibits dietary lipid uptake in vivo. Rats were fasted for 4 h before treatment with a 10mg/kg I.P. injection of either saline control, Lovastatin, or Lovastatin-hydroxyacid (HA) 1 hr prior to being gavaged with a bolus of Bodipy-FL16 combined with oleic acid. 1 h after the bolus was given, (Ai) mesenteric lymph nodes (MLN), (Aii) blood, and (Aiii) feces were collected and analyzed for Bodipy content (see Methods). Additionally, fluid retention within the (B) ileum (ILE) and (C) MLNs were determined by wet/dry weight analysis. Data are presented as mean ± SEM of 5 rats over 5 independent experiments. ** p < 0.01, *** p < 0.001 vs. sham One-way ANOVA with Dunnet's multiple comparison test.
Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus

October 2021

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75 Reads

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5 Citations

International Journal of Molecular Sciences

Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin-or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin's effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.


NR4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts

July 2021

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120 Reads

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37 Citations

AJP Gastrointestinal and Liver Physiology

Background: Intestinal fibrosis is a common complication of the inflammatory bowel diseases(IBD), contributing to tissue stiffening and luminal narrowing. NR4A1 was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Methods: Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling: cytosporone B(Csn-B) or 6-mercaptopurine(6-MP); could reduce fibrosis. We also employed the dextran sulphate sodium(DSS) model of colitis and assessed the magnitude of colonic fibrosis in Nr4a1-/- and their wild-type littermates(Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-beta-1(TGF-β1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed. Results: Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-β1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was anti-proliferative in Nr4a1+/+, but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-β1-induced collagen deposition and fibrosis-related gene expression. Conclusions: Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.


Differentiated M1 and M2 macrophage expression of TLR4 in vitro. PMA differentiated THP-1 monocytes (Resting M0-Macrophages) were stimulated for 24 h with either (50 ng/ml) recombinant human IFNγ (M1 polarization) or 25 ng/ml each of recombinant human IL-4 and IL-13 (M2). Polarity of matching sets of macrophages were initially confirmed by (A) qPCR analysis for (Ai) M1 markers: CXCL10, CCR7, IL-12 or (Aii) M2 markers: CD206, CD163, CCL17. Cell surface expression of (B) CD14 or (C) TLR4 was determined through flow cytometric analysis. Further analysis of total expression of TLR4 through permeabilization of cells and comparison to cell surface staining reveals (D) Abundance of TLR4 on the surface or total (including internal) of M1 and M2 polarized THP-1 macrophages. (E) Single colour immunofluorescent confocal microscopy images of TLR4 expression within (Ei) M0, (Eii) M1, (Eiii) M2 macrophages show differential patterns of staining within the cells. Images are a representative of 3 independent experiments. qPCR data is expressed as the mean ± SEM of 3 independent differentiations of THP-1 derived macrophages of passages 5–8. (Histograms: Pink-isotype control, Blue—THP-1 monocyte controls, Green and Dark Green—M0 macrophages, Purple and Blue—M1 macrophages, Dark and light grey—M2 macrophages). Scale bar = 20 µm. Statistical analysis performed on qPCR data was a two tailed multiple unpaired students t-test comparing stimulated to control, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Differential M1 and M2 macrophage de novo NF-κB and IRF3 induction and cytokine production in response to LPS species. PMA differentiated THP-1 monocytes (Resting M0-Macrophages) were stimulated for 24hrs with either (50 ng/ml) recombinant human IFNγ (M1 polarization) or 25 ng/ml each of recombinant human IL-4 and IL-13 (M2). Macrophages were challenged with 1 ng/ml LPS in complete media for up to 24 h after which supernatants were collected for (Ai–v) multiplex cytokine (Il-1B, IL-6, IL-9, IL-10, TNFα), (vi) representative MTT viability assay experiment. Data is expressed as the mean ± SEM of 3 independent differentiations of THP-1 derived macrophages of passages 5–8. Mean ± SD is displayed for MTT. Statistical analysis performed on qPCR data was a multiple unpaired students t-tests comparing stimulated to control, **P < 0.01, ***P < 0.001, ****P < 0.0001.
E. coli and S. enterica, but not P. aeruginosa LPS signal partially via the endosome in polarized macrophages resulting in altered inflammatory cytokine production. Differentiated M1 THP-1 macrophages were stimulated with LPS from P. aeruginosa, E. coli or S. enterica with or without pre-incubation with 100 µM Hydroxy-Chloroquine. Induction of (A) LPS induced P65 phosphorylation measured after 30 min with/without Clq (Hydroxychloroquine). (B–E) IP-10, TNFα, IL-6 and IL-8 production was measured in conditioned supernatants. Data is expressed as the mean ± SEM of 3 independent differentiations of THP-1 derived macrophages of passages 5–8. Statistical analysis performed on qPCR data was a one-way ANOVA with Tukeys posthoc test, **P < 0.01, ****P < 0.0001.
LPS-driven phosphorylation of P65 and IRF3 is species specific and TAK1 and/or TBK1 dependent. Cells were then lysed and assayed for (Ai) phospho-P65, total p65, phospho-IRF3, total IRF3 and B-Actin acting as a loading control (Upper panel is a representative of n = 3 experiments). (Aii) Phosphorylated P65 and IRF3 were analysed in comparison to total P65 or IRF3 respectively. Data is represented as mean ± SEM of 3 separate stimulations performed on IFNγ differentiated M1 macrophages Passage 6–9. (B) Graphical representation of proposed signalling dynamics of the individual LPS via TLR4 and targets for TAKINIB or MRT67307 inhibitors. Cells were stimulated with LPS (1 ng/ml) with or without 1 h pre-treatment with TAKINIB (10 µM) or MRT67307 (10 µM) for 30 min in serum starved conditions. Membranes were stripped and re-probed, or cut longitudinally, to probe multiple antibodies within the same membrane, full-uncropped images can be found in Supplemental Fig. S1. The images in figure are from 2 separate gels and membranes. Statistical analysis performed on qPCR data was a one-way ANOVA with Tukeys posthoc test **P < 0.01, ***P < 0.001, ****P < 0.0001. Illustration created using Biorender.com. Figure generated by MS with permissions granted for publication.
Ultra-purification of Lipopolysaccharides reveals species-specific signalling bias of TLR4: importance in macrophage function

January 2021

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575 Reads

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15 Citations

TLR4 location, and bacterial species-derived lipopolysaccharides, play a significant role in the downstream activation of transcription factors, accessory molecules, and products. Here, this is demonstrated through the use of classically-activated and alternatively-activated macrophages. We show that, when polarized, human macrophages differentially express and localize TLR4, resulting in biased recognition and subsequent signalling of LPS derived from Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica . Analysis of activation demonstrated that in classically activated macrophages, P. aeruginosa signals from the plasma membrane via TLR4 to p65 dependent on TAK1 and TBK1 signalling. E. coli signals dependent or independent of the endosome, utilizing both TAK1- and TBK1-signalling to induce P65 and IRF3 inducible genes and cytokines. S. enterica however, only induces P65 and IRF3 phosphorylation through signalling via the endosome. This finding outlines clear signalling mechanisms by which innate immune cells, such as macrophages, can distinguish between bacterial species and initiate specialized responses through TLR4.


Citations (63)


... Utilizing rat diaphragmatic lymphatic vessels, Solari et al. demonstrated important roles for TRPV4 channels in modulating lymphatic contractility by means of sensing changes in temperature and osmolarity 35,36 . Recently, TRPV4 channels were shown to play a critical role in flow-mediated downregulation of the contractile frequency of rat mesenteric lymphatic vessels in association with production of nitric oxide and vasodilatory prostanoids 37 . ...

Reference:

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells
Flow-dependent regulation of rat mesenteric lymphatic vessel contractile response requires activation of endothelial TRPV4 channels
  • Citing Article
  • December 2023

Microcirculation (New York, N.Y.: 1994)

... Furthermore, the expression of genes related to inflammatory responses (Fig. 3E), such as Cxcl2, Cxcl3, Cxcl10, Il1b, Sod2, S100a9, Saa3, Hp [37], Ifitm3 [38], Fcer1g [39], and Clec4e [40] was upregulated on day 3 after LPS administration. These genes were expressed mainly in club cells, followed by AT1 and AT2 cells. ...

Mincle-binding DNA aptamer demonstrates therapeutic potential in a model of inflammatory bowel disease

Molecular Therapy — Nucleic Acids

... The inhibitory effect of simvastatin on Src was further corroborated in another study (Kim et al., 2009). Other studies have also highlighted the inhibitory effects of statins on other kinases (Erstad & Cusack, 2013;Stephens et al., 2021). Interestingly, inhibition of the EGFR/Src pathway has been linked to the down-regulation of HMGCR (Yun et al., 2019) and may also potentially impact mitochondrial function (Cao et al., 2011;Demory et al., 2009) ...

Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus

International Journal of Molecular Sciences

... Recently, great achievements have been made in understanding molecular and cellular mechanisms related to intestinal fibrosis during IBD. Intestinal myofibroblasts and Th17 cells exert vital impacts on occurrence and development of intestinal fibrosis by interacting with profibrogenic pathways and cytokines to induce and maintain the fibrotic response [10,11]. Moreover, genetic variants in cytokine genes, immunoregulatory proteins, and epigenetic factors have been implicated in intestinal fibrosis and IBD [12][13][14][15]. ...

NR4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts

AJP Gastrointestinal and Liver Physiology

... A previous study identified particulate wear debris from in vivo prosthesis degradation as a crucial factor stimulating the release of proinflammatory substances, suppressing bone formation, inducing osteoclastic bone resorption, and contributing to prosthesis-related chronic inflammation (3). Therefore, a deeper understanding of the impact of prosthesis material design and particulate wear debris on the inflammatory response after joint replacement is essential for preventing aseptic loosening and periprosthetic osteolysis (4). among various biomaterials, titanium (Ti)-based implants are the most widely used in the medical field, including dental prostheses, hearing aids, pacemakers and joint replacements (5). it is well established that oral peri-implant and periodontal bone loss, primarily caused by peri-implantitis and periodontitis, and wear debris, particularly Ti particles near the implant site, are crucial triggers of inflammation and bone resorption (6). ...

Ultra-purification of Lipopolysaccharides reveals species-specific signalling bias of TLR4: importance in macrophage function

... It may be associated with certain genes mutation (likely VEGFR3, PROX1, FOXC2, and SOX18) that are involved in lymphatic development [8] . Mutations in these genes often result in lymphatic malformations, defective valve formation, and altered cellcell adhesion, leading to lymphedema through vessel occlusion, dilation, loss of functional lymphatics, or fibrosis [13] . The Table 1 illustrates the consequences of mutations of these genes and their respective roles in the development of PIL. ...

Lymphatic pumping and pathological consequences of its dysfunction
  • Citing Chapter
  • January 2020

... Like vascular smooth muscle, lymphatic muscle cells respond to regulation by nitric oxide, prostaglandins, and histamine [22]. Lymphatic pumping is initiated in the smooth muscle cells by a pacemaker mechanism generating voltage-gated Ca 2+ channel-induced action potentials, which supplies the depolarization and influx of Ca 2+ necessary for the contractile mechanisms to induce the phasic constrictions of lymphangions and forward movement of lymph [22,63]. These cardiovascular similarities can explain drug interactions and adverse effects on the lymphangion contractile function [64]. ...

Lymphatic Vessel Pumping
  • Citing Chapter
  • June 2019

Advances in Experimental Medicine and Biology

... In preclinical models of sepsis, changes in tight junctions were observed after 1 hour of sepsis onset, with intestinal hyperpermeability persisting for at least 48 hours (125). LPS, a component of the outer wall of Gram-negative bacteria, alters TJ protein assembly, leading to small intestinal leakage, and regulates the inflammatory response through TLR4, further aggravating the changes in TJ (129). S1P has been described as a barrier-enhancing molecule (130). ...

Lipopolysaccharides modulate intestinal epithelial permeability and inflammation in a species-specific manner
  • Citing Article
  • June 2019

... The DAI was determined by combining scores from three categories: body weight loss, stool consistency, and the presence of blood in the stool [27,28]. Rectal bleeding are shown in Figure 2 [29]. ...

Mesenteric Lymphatic Alterations Observed During DSS Induced Intestinal Inflammation Are Driven in a TLR4-PAMP/DAMP Discriminative Manner