TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung

JCI Insight
Swati BhattacharyyaJohn Varga

Abstract

Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc sk...Continue Reading

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Citations

Feb 27, 2019·Archives of Dermatological Research·Jakub ŻółkiewiczLidia Rudnicka
Feb 13, 2020·Clinical and Experimental Immunology·L Frasca, R Lande
Nov 16, 2019·Lymphatic Research and Biology·Mirko BaglivoMatteo Bertelli
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Dec 10, 2019·Journal of Immunology Research·Lixiang SunLing-Juan Zhang
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Apr 26, 2020·Cellular Signalling·Peder Öhman FuchsPär Gerwins
Feb 22, 2021·Journal of Cellular and Molecular Medicine·Zeyuan SongMingshun Zhang
Apr 15, 2021·Advanced Biology·Andrea De PieriKarin Wuertz-Kozak
Jun 3, 2021·Pediatric Pulmonology·Kun YangWenbin Dong
Jun 20, 2021·Cellular and Molecular Life Sciences : CMLS·Hamid Mattoo, Shiv Pillai
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Aug 10, 2021·Frontiers in Immunology·Siavash BolouraniPing Wang
Oct 9, 2021·Cell Stem Cell·Hesham SolimanFabio M V Rossi
Dec 26, 2021·Journal of Cellular and Molecular Medicine·Peng ZhongHe Huang

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Datasets Mentioned

BETA
GSE59785
GSE79621
GSE32413

Methods Mentioned

BETA
biopsies
chips
biopsy
Assay
PCR
transfection
confocal microscopy
ELISA

Software Mentioned

Living Image
Illumina Bead version
Graph Pad prism
US
Graph Pad
ImageJ
Bioconductor lumi package
R

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