Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

Bhattacharyya, Swati; Midwood, Kim S.; Yin, Hang; Varga, John

doi:10.1089/wound.2017.0732

Cited by 60 publications

(71 citation statements)

References 80 publications

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“…Myd88 is known to facilitate TLR mediated signaling of various damage-associated molecular patterns (DAMPs) in certain instances of wounding or cancer (see 45 – 47 for recent reviews). However, while DAMP signaling cannot be conclusively excluded, the absence of any obvious cause of tissue damage in the germ-free embryos, and the lack of evidence for the induction of inflammatory cytokines seems to argue against DAMP driven signaling as a cause, as they are generally considered proinflammatory in nature 45 – 47 . Rather, we propose that the elevated myd88 could be the driver of a ligand independent response characterized by induction of the genes encoding the CCAAT/enhancer binding proteins and AP1 transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Intestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88

et al. 2018

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Host pathways mediating changes in immune states elicited by intestinal microbial colonization are incompletely characterized. Here we describe alterations of the host immune state induced by colonization of germ-free zebrafish larvae with an intestinal microbial community or single bacterial species. We show that microbiota-induced changes in intestinal leukocyte subsets and whole-body host gene expression are dependent on the innate immune adaptor gene myd88. Similar patterns of gene expression are elicited by colonization with conventional microbiome, as well as mono-colonization with two different zebrafish commensal bacterial strains. By studying loss-of-function myd88 mutants, we find that colonization suppresses Myd88 at the mRNA level. Tlr2 is essential for microbiota-induced effects on myd88 transcription and intestinal immune cell composition.

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Section: Discussionmentioning

confidence: 99%

Intestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88

et al. 2018

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“…We have shown previously that both fibronectin-EDA and tenascin-C are markedly upregulated and colocalize with activated myofibroblasts in skin and lung biopsies from patients with SSc (12)(13)(14). Furthermore, these DAMPs have the capacity to stimulate the expression of ECM genes and promote myofibroblast transformation, cell migration, and mechanical force generation in mesenchymal cells (34). The present studies indicate that TLR4 and MD2 were markedly upregulated in a subset of SSc skin biopsies; and levels showed a strong correlation with the TLR4 gene signature within the same biopsies.…”

Section: Discussionmentioning

confidence: 94%

“…Persistent fibroblast activation underlies unresolving skin and lung fibrosis in SSc and represents a major barrier to effective therapy. While immune cells within lesional tissue are prominent in early-stage disease, chronic fibrosis is largely pauci-inflammatory, indicating a role for immune cell-independent factors in maintaining the activated state of fibroblasts (34). In particular, DAMPs generated within the fibrotic Each dot represents mean ± SD from triplicate determination from 3 mice per group.…”

Section: Discussionmentioning

confidence: 99%

“…Deregulated TLR signaling is implicated in chronic inflammatory diseases, autoimmunity, and cancer (35). While TLRs are best characterized on BM-derived cells of the immune system, they are also expressed in tissue-resident stromal cells, where they play key roles in tissue homeostasis and repair, but also contribute to the persistence of sterile inflammatory responses underlying chronic diseases (34). Uniquely among the surface TLRs, TLR4 activation by LPS and other exogenous ligands requires accessory receptor MD2 (6).…”

Section: Discussionmentioning

confidence: 99%

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

Bhattacharyya

Wang²,

Qin

et al. 2018

JCI Insight

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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.

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“…The Toll-like receptors have until recently been considered to mediate only innate immune responses but have lately been shown to bind endogenous ligands such as hyaluronan (41), HMGB1 (42) and fibrinogen (30). Although TLR4 is mainly expressed by immune cells as part of the innate immune system, TLR4 activation has also been shown to occur in non-immune cells within injured tissue micro-environments, such as renal fibrosis (43) and scleroderma (44,45). Our data now suggests that TLR4 modulates FnEstimulated fibroblast migration.…”

Section: Discussionmentioning

confidence: 99%

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Fuchs

Heindryckx

Calitz

et al. 2019

Preprint

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SummaryBackgroundFibrin is an essential constituent of the coagulation cascade, and the formation of hemostatic fibrin clots is central to wound healing. Fibrin clots are over time degraded into fibrin degradation products as the injured tissue is replaced by granulation tissue.Objectivesstudy the role of the fibrin degradation product fragment E (FnE) in fibroblast activation and migration.MethodsRat kidney fibroblasts (NRK-49F), human fetal lung fibroblasts (HFL1) and immortalized human foreskin fibroblasts (BJ) were exposed to FnE and TGF-β. Fibroblast activation was measured via quantitative RT-PCR and western blot for α-SMA and Collagen Iα1. A microfluidic chemotaxis assay was used to study directional migration. To investigate if FnE interacts with integrins, direct binding experiments were performed using surface plasmon resonance biosensor technology. Infusion pumps releasing FnE were implanted subcutaneously in mice and profibrotic effects of FnE were analyzed using immunohistochemical staining of the wound area.ResultsWe present evidence that FnE is a chemoattractant for fibroblasts and that FnE can potentiate TGF-β-induced myofibroblast formation. FnE forms a stable complex with αVβ3 integrin, and the integrin β3 subunit is required both for FnE-induced fibroblast migration and for potentiation of TGF-β-induced myofibroblast formation. Finally, subcutaneous infusion of FnE in mice results in a fibrotic response in the hypodermis. These results support a model where FnE released from clots in wounded tissue promote wound healing and fibrosis by both recruitment and activation of fibroblasts. Fibrin fragment E could thus represent a therapeutic target for treatment of pathological fibrosis.Essentials–Fibrin is an essential constituent of the coagulation cascade, and fibrin clotting is central to wound healing.–Fibrin clots are over time degraded into fibrin degradation products, including fibrin fragment E (FnE).–FnE is a chemoattractant for fibroblasts and can potentiate TGF-β-induced myofibroblast formation.–FnE released from clots in wounded tissue could promote wound healing and fibrosis.

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Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

Cited by 60 publications

References 80 publications

Intestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88

Intestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88

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

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

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