LTBP4 in Health and Disease

Su, Chi-Ting; Urbán, Zsolt

doi:10.3390/genes12060795

Cited by 27 publications

(21 citation statements)

References 74 publications

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“…TGFβ is secreted inactive and bound to latent TGFβ binding proteins (LTBP1-4), together forming the large latent complex (LLC) (57). Activation of TGFβ occurs via a tightly controlled process, involving cleavage of the LTBPs, or protease-independent via integrins (57, 58). We therefore wondered, if PBMCsec also regulates molecules indirectly involved in TGFβ-activation.…”

Section: Resultsmentioning

confidence: 99%

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

Vorstandlechner

Copic

Klas

et al. 2022

Preprint

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Background Hypertrophic scars can cause pain, movement restrictions, and reduction of quality of life. Despite numerous options to tackle hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Secreted factors from peripheral blood mononuclear cells (PBMCsec) were previously described for their beneficial effects in tissue regeneration. Here, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single cell resolution (scRNAseq). Methods Mouse wounds and scars were treated with PBMCsec either intradermally or topically. Human mature scars were treated with PBMCsec ex vivo in explant cultures. All experimental settings were analyzed by single cell RNA sequencing (scRNAseq). A variety of bioinformatics approaches were used to decipher gene regulation in the scRNAseq data sets. Components of the extracellular matrix (ECM) were investigated in situ by immunofluorescence. The effect of PBMCsec on myofibroblast differentiation and elastin expression was investigated by stimulating human primary fibroblasts with TGFβ. Findings Topical and intradermal application of PBMCsec regulated the expression of a variety of genes involved in pro-fibrotic processes and tissue remodeling. Our bioinformatics approach identified elastin as a common linchpin of antifibrotic action in both, the mouse and human experimental setting. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast-differentiation and attenuates abundant elastin expression through non-canonical signaling inhibition. Furthermore, TGFβ-induced breakdown of elastic fibers was strongly inhibited by addition of PBMCsec. Interpretation Together, we showed anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings, suggesting PBMCsec as a novel therapeutic option to treat skin scarring.

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Section: Resultsmentioning

confidence: 99%

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

Vorstandlechner

Copic

Klas

et al. 2022

Preprint

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“…Involved mechanisms may include altered signaling activities by direct binding, complex formation, competitive inhibition, induction or repression of secondary mediators and others. In this regard, other circulating proteins besides Postn, TGFBi and Reln are likely involved in the disease pathogenesis including the identified candidates H6PD 60 , COL18A1, HSPG2 61 , GPX3 62 , GPC1 63 , FBLN2 64 , PTX3 65 , LTBP4 66 , CLEC11A and DKK3 67-69 , most of which have been implicated in atherosclerosis and cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Targeting of scavenger receptors Stabilin-1 and Stabilin-2 ameliorates atherosclerosis by a plasma proteome switch mediating monocyte/macrophage suppression

Manta

Leibing

Friedrich

et al. 2022

Preprint

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Background: Scavenger receptors (SR) Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may impact atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. Methods: ApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet (WD). For antibody targeting, Ldlr-KO mice were also used. Unbiased plasma proteomics were performed and independently confirmed. Ligand binding studies comprised GST-pull down and endocytosis assays. Plasma proteome effects on monocytes were studied by single cell RNA sequencing in vivo, and by gene expression analyses of Stabilin-ligand-stimulated and plasma-stimulated bone marrow-derived monocytes/macrophages (BMDM) in-vitro. Results: Spontaneous and WD-associated atherogenesis was significantly reduced in ApoE-Stab1- and ApoE-Stab2-KO. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies (mAB) significantly reduced WD-associated atherosclerosis in ApoE-KO and Ldlr-KO. While neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing Wildtype with Stab1/2 single and Stab1/2-double KO, and of 41 proteins comparing ApoE-, ApoE-Stab1- and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate SR ligand candidates, Periostin, Reelin and TGFBi, known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. scRNA-Seq of circulating myeloid cells of ApoE-, ApoE-Stab1- and ApoE-Stab2-KO showed transcriptomic alterations in patrolling (Ccr2-/Cx3cr1++/Ly6Clo) and inflammatory (Ccr2+/Cx3cr1+/Ly6Chi) monocytes including downregulation of pro-atherogenic transcription factor Egr1. In Wildtype BMDM, ligand exposure alone did not alter Egr1 expression in-vitro. However, exposure to plasma from ApoE-Stab1- and ApoE-Stab2-KO mice showed a reverted pro-atherogenic macrophage activation as compared to ApoE-KO plasma including downregulation of Egr1 in-vitro. Conclusions: Inhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome including direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory monocytes and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1- and anti-Stab2-targeted therapies provide a novel approach for the future treatment of atherosclerosis.

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“…The GO term enrichment analysis of cluster 7 showed a positive regulation of cytokine production and a positive response to pro-inflammatory cytokines, in addition to ERK1/2 signaling cascade activation, implicated in many pathological conditions associated with chronic inflammation (Figure S4F). Cluster 8, predominantly derived from cells in the DT aorta in NCD (Figure S2D), emerged as a population showing a gene expression profile characterized by the expression of Ltbp4 an essential regulator of TGFβ signaling, which is related to development, immunity, injury repair, and diseases, as well as playing a central role in regulating inflammation and fibrosis [49] (Figure 2G). Furthermore, cluster 8 also expressed genes like Clu (clusterin) with a role in complement inhibition, inflammation regulation, lipid transport, apoptosis, and cell differentiation [50].…”

Section: Atherosclerosis Cluster Gene Expression Signaturesmentioning

confidence: 99%

Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells

Burger

Baptista

Roth

et al. 2022

Cells

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Background: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. Methods: A single-cell RNA sequencing analysis of CD45+ leukocytes in the atherosclerotic aorta of apolipoprotein E–deficient (Apoe−/−) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the side-to-specific predisposition to atherosclerosis, was performed. A population of res-like macrophages expressing hyaluronan receptor LYVE-1 was investigated via flow cytometry, co-culture experiments, and immunofluorescence in human atherosclerotic plaques from carotid artery disease patients (CAD). Results: We identified 12 principal leukocyte clusters with distinct atherosclerosis disease-relevant gene expression signatures. LYVE-1+ res-like macrophages, expressing a high level of CC motif chemokine ligand 24 (CCL24, eotaxin-2), expanded under hypercholesteremia in Apoe−/− mice and promoted VSMC phenotypic modulation to osteoblast/chondrocyte-like cells, ex vivo, in a CCL24-dependent manner. Moreover, the abundance of LYVE-1+CCL24+ macrophages and elevated systemic levels of CCL24 were associated with vascular calcification and CAD events. Conclusions: LYVE-1 res-like macrophages, via the secretion of CCL24, promote the transdifferentiation of VSMC to osteogenic-like cells with a possible role in vascular calcification and likely a detrimental role in atherosclerotic plaque destabilization.

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LTBP4 in Health and Disease

Cited by 27 publications

References 74 publications

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

The secretome of irradiated peripheral mononuclear cells attenuates hypertrophic skin scarring

Targeting of scavenger receptors Stabilin-1 and Stabilin-2 ameliorates atherosclerosis by a plasma proteome switch mediating monocyte/macrophage suppression

Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells

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