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TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung
Swati Bhattacharyya, … , Hang Yin, John Varga
Swati Bhattacharyya, … , Hang Yin, John Varga
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e98850. https://doi.org/10.1172/jci.insight.98850.
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Research Article Pulmonology

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

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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 skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.

Authors

Swati Bhattacharyya, Wenxia Wang, Wenyi Qin, Kui Cheng, Sara Coulup, Sherry Chavez, Shuangshang Jiang, Kirtee Raparia, Lucia Maria V. De Almeida, Christian Stehlik, Zenshiro Tamaki, Hang Yin, John Varga

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Figure 1

Upregulated TLR4 and coreceptor MD2 in SSc skin biopsies.

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Upregulated TLR4 and coreceptor MD2 in SSc skin biopsies.
(A) Expression...
(A) Expression microarray datasets (GSE9285, GSE32413, GSE45485, and GSE59785) were queried for TLR4 and MD2 levels. Results are shown as box plots (25th to 75th percentile; horizontal lines represent median, maximum, and minimum values). H, healthy; L, limited; I, inflammatory; P, diffuse proliferative intrinsic subset. One-way ANOVA followed by Sidak’s multiple comparison test. (B) Correlation of MD2 with TLR4 levels. Each dot is a single biopsy. Spearman’s rank correlation. (C and D) MD2 and TLR4 levels correlate with TLR4 signature scores (GSE24125) (20). Spearman’s rank correlation.

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