Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

Izadi, David; Layton, T. B.; Williams, Lynn M.; McCann, Fiona E.; Cabrita, Marisa; Santo, Ana I. Espirito; Xie, Weilin; Fritzsche, Marco; Colin‐York, Huw; Feldmann, Marc; Midwood, Kim S.; Nanchahal, Jagdeep

doi:10.1126/sciadv.aay0370

Cited by 26 publications

(36 citation statements)

References 41 publications

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“…Furthermore, we show that collagen VI regulates expression of the chemokines CCL2, CCL7, and CCL26, in accordance with previous data suggesting a potential role of endotrophin (ETP) in chemotaxis (60), and we confirmed a role of collagen VI in myofibroblast-induced chemotaxis of THP1 cells. Previously (4), we identified macrophages and mast cells as the predominant source of TNF within Dupuytren's nodule cultures and demonstrated that macrophage-derived TNF plays a key role in promoting the fibrotic phenotype in Dupuytren's disease (4). Excessive production of collagen VI may contribute to the chronicity of the disease by promoting the recruitment of monocytic cells to the site of this disease and probably plays a similar role in other fibrotic disorders (61).…”

Section: Discussionmentioning

confidence: 86%

“…Using the relatively early-stage nodules from patients with Dupuytren’s disease enables us to analyze signaling and regulatory pathways and hence has the potential for the identification of novel therapeutic targets. Dupuytren’s nodules represent a complex disease system, housing densely packed myofibroblasts (MFs) alongside other less abundant stromal and immune cells ( 4 ). Myofibroblasts are characterized by the expression of α-smooth muscle actin (α-SMA) and excessive production of extracellular matrix (ECM) proteins such as collagens, glycoproteins, and proteoglycans, which enhances their ability to contract tissue ( 5 , 6 ).…”

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confidence: 99%

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Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the study primarily focused on the combined effects of TNF-α and IL-33, we believe it supports our findings. Izadi and colleagues did not record much spontaneous IL-13 release ( 11 ), which may be due to cells being latent following disaggregation from tissue; IL-33 is known to drive IL-13 release from mast cells in disease ( 43 ). The current study has demonstrated that IL-13 release and its downstream fibrotic effects are viable targets for therapy.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Dupuytren’s fibrosis via targeting of the STAT1 modulated IL-13Rα1 response

et al. 2020

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Fibrotic disorders represent common complex disease pathologies that are therapeutically challenging. Inflammation is associated with numerous fibrotic pathogeneses; however, its role in the multifaceted mechanisms of fibrosis remains unclear. IL-13 is implicated in aberrant responses involved in fibrotic disease, and we aimed to understand its role in the inflammatory processes of a common fibrotic disorder, Dupuytren’s disease. We demonstrated T-cells produced IFN-g, which induced IL-13 secretion from mast cells and up-regulated IL-13Ra1 on fibroblasts, rendering them more reactive to IL-13. Consequently, diseased myofibroblasts demonstrated enhanced fibroproliferative effects upon IL-13 stimulation. We established IFN-g and IL-13 responses involved STAT dependent pathways, and STAT targeting (tofacitinib) could inhibit IL-13 production from mast cells, IL-13Ra1 up-regulation in fibroblasts and fibroproliferative effects of IL-13 on diseased myofibroblasts. Accordingly, utilizing Dupuytren’s as an accessible human model of fibrosis, we propose targeting STAT pathways may offer previously unidentified therapeutic approaches in the management of fibrotic disease.

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“…Research showed that Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, can ameliorate chronic kidney disease through mitigating TNF-mediated tissue injury and fibrosis [ 50 ]. Moreover, TNF- α can stimulate IL-33 secretion via interaction with TNFR2 and which promotes myofibroblast development to accelerate the process of myocardial fibrosis [ 51 ]. NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor, MCC950, is first demonstrated to ameliorate nonalcoholic fatty liver disease (NAFLD) and fibrosis in obese diabetic mice, and the targeting of NLRP3 is a logical direction in pharmacotherapy for liver fibrosis [ 54 ].…”

Section: Molecular and Cellular Mechanisms Of Fibrosismentioning

confidence: 99%

Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

Chen

Yuan

Cao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Fibrosis is defined as the pathological progress of excessive extracellular matrix (ECM), such as collagen, fibronectin, and elastin deposition, as the regenerative capacity of cells cannot satisfy the dynamic repair of chronic damage. The well-known features of tissue fibrosis are characterized as the presence of excessive activated and proliferated fibroblasts and the differentiation of fibroblasts into myofibroblasts, and epithelial cells undergo the epithelial-mesenchymal transition (EMT) to expand the number of fibroblasts and myofibroblasts thereby driving fibrogenesis. In terms of mechanism, during the process of fibrosis, the activations of the TGF-β signaling pathway, oxidative stress, cellular senescence, and inflammatory response play crucial roles in the activation and proliferation of fibroblasts to generate ECM. The deaths due to severe fibrosis account for almost half of the total deaths from various diseases, and few treatment strategies are available for the prevention of fibrosis as yet. Recently, numerous studies demonstrated that three well-defined bioactive gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), generally exhibited anti-inflammatory, antioxidative, antiapoptotic, and antiproliferative properties. Besides these effects, a number of studies have reported that low-dose exogenous and endogenous gasotransmitters can delay and interfere with the occurrence and development of fibrotic diseases, including myocardial fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, diabetic diaphragm fibrosis, and peritoneal fibrosis. Furthermore, in animal and clinical experiments, the inhalation of low-dose exogenous gas and intraperitoneal injection of gaseous donors, such as SNAP, CINOD, CORM, SAC, and NaHS, showed a significant therapeutic effect on the inhibition of fibrosis through modulating the TGF-β signaling pathway, attenuating oxidative stress and inflammatory response, and delaying the cellular senescence, while promoting the process of autophagy. In this review, we first demonstrate and summarize the therapeutic effects of gasotransmitters on diverse fibrotic diseases and highlight their molecular mechanisms in the process and development of fibrosis.

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Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis

Abstract: IL-33 mediates cross-talk between immune and stromal cells in localized fibrosis.

Cited by 26 publications

References 41 publications

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Attenuation of Dupuytren’s fibrosis via targeting of the STAT1 modulated IL-13Rα1 response

Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases

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