Deficiency in the LIM-only protein Fhl2 impairs skin wound healing

Wixler, Viktor; Hirner, Stephanie; Müller, Judith; Gullotti, Lucia; Will, Carola; Kirfel, Jutta; Günther, Thomas; Schneider, Holm; Bosserhoff, Anja‐Katrin; Schorle, Hubert; Park, Jung; Schüle, Roland; Buettner, Reinhard

doi:10.1083/jcb.200606043

Cited by 78 publications

(118 citation statements)

References 27 publications

(55 reference statements)

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“…This effect was also described previously concerning the role of fibroblasts in wound healing. 9 These data point to an important role of FHL2 in migration of fibroblasts in general. Furthermore, we showed that treatment of fibroblasts with TGF-b1 went along with a higher number of cells with the capacity to migrate, a finding which has also been reported in the literature before.…”

Section: Fhl2 Expression In Colon Cancermentioning

confidence: 89%

“…We previously determined an important role of FHL2 in myofibroblasts during wound healing. 9 It has been shown that wounded tissue is comparable in several aspects to the tumour stroma as both are characterised by activated, a-SMA-expressing myofibroblasts and deposition of provisional matrix and basal membrane molecules. 11 As previous studies 19,28 described an induction of FHL2 expression by TGF-b1, this study considered both markers in the systematic analysis of colorectal tumour tissue and tumour stroma in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…7,34 Myofibroblasts coexpressed a-SMA and FHL2 with a characteristic expression pattern of FHL2 at focal adhesion contacts as also observed in wounded tissue. 9 It is therefore likely that TGF-b1-induced, FHL2 overexpressing myofibroblasts form a highly mobile tumour stroma favouring migration, invasive growth and dissemination of colon cancer cells. The leading role of myofibroblasts in invasive growth of carcinomas has recently been described by Gaggioli et al, 35 who found that squamous cell carcinoma cells move collectively within tracks in the extracellular matrix behind the leading fibroblast remodelling the extracellular matrix.…”

Section: Fhl2 Expression In Colon Cancermentioning

confidence: 99%

“…9 Mouse fibroblasts were plated onto 15 cm dishes and grown to 75% confluency in DMEM supplemented with 10% FCS. Then the cells were grown in low serum (DMEM supplemented with 0.5% FCS) for 48 h and treated with 2 ng/ml recombinant human TGF-b1 (Tebu, Offenbach, Germany) in low serum conditions for different time points (0, 24, 72 and 96 h).…”

Section: Tissue Culturementioning

confidence: 99%

“…[6][7][8] We showed previously that FHL2 is strongly upregulated in mesenchymal cells of wounded skin, and demonstrated a function of FHL2 in myofibroblasts regulating their migration and contraction during cutaneous wound healing. 9 Furthermore, FHL2 is critically involved in matrix assembly allowing migration of cells into the wound area. 10 Analogous to wound healing invasive carcinomas generate a specialised tumour stroma and deposit a matrix facilitating invasion into the surrounding tissue.…”

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FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-b1 ligand and a-SMA. Myofibroblasts at the tumour invasion front co-expressed a-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-b1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-b1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-b. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-b1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas. Four and a half LIM domain protein-2 (FHL2) was first identified as a protein differentially expressed in human myoblasts and rhabdomyosarcoma cells, and thus named DRAL (downregulated in rhabdomyosarcoma LIM protein 1 ). FHL2 is a LIM-only protein with four complete and one N-terminal half LIM domains that mediate protein-protein interactions. 2 FHL2 associates with integrin receptors to form focal adhesion contacts and binds signal transducers such as b-catenin. 3-5 Triggered by lipid-induced signalling, such as sphingosine-1-phosphate, FHL2 translocates into the nucleus where it binds several transcription factors including serum response factor, AP1 and androgen receptor and functions as a coactivator or a corepressor to modulate gene expression. [6][7][8] We showed previously that FHL2 is strongly upregulated in mesenchymal cells of wounded skin, and demonstrated a function of FHL2 in myofibroblasts regulating their migration and contraction during cutaneous wound healing. 9 Furthermore, FHL2 is critically involved in matrix assembly allowing migration of cells into the wound area. 10 Analogous to wound healing invasive carcinomas generate a specialised tumour stroma and de...

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Section: Fhl2 Expression In Colon Cancermentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Fhl2 Expression In Colon Cancermentioning

confidence: 99%

Section: Tissue Culturementioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension

Hsu¹,

Shi²,

Jordan³

et al. 2011

Arthritis & Rheumatism

197

159

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Objective. Pulmonary complications, including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality in patients with systemic sclerosis (SSc). The aim of this study was to compare the molecular fingerprint of lung tissue and matching primary fibroblasts from patients with SSc with that of lung tissue and fibroblasts from normal donors, patients with idiopathic pulmonary fibrosis (IPF), and patients with idiopathic pulmonary arterial hypertension (IPAH).Methods. Lung tissue samples were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, and patients with IPAH. Microarray data were analyzed using efficiency analysis for determination of the optimal data-processing methods. Real-time polymerase chain reaction and immunohistochemistry were used to confirm differential levels of messenger RNA and protein, respectively.Results. Consensus efficiency analysis identified 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. SSc-PF and IPF lungs shared enriched functional groups in genes implicated in fibrosis, insulin-like growth factor signaling, and caveolin-mediated endocytosis. Gene functional groups shared by SSc-PAH and IPAH lungs included those involved in antigen presentation, chemokine activity, and interleukin-17 signaling.Conclusion. Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts from patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease specific (SSc) and phenotype specific (PF versus PAH). These signatures provide new insights into the pathogenesis and potential therapeutic targets of SScrelated lung disease.

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LIM‐only protein FHL2 regulates experimental pulmonary Schistosoma mansoni egg granuloma formation

et al. 2015

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LIM-only protein FHL2 is associated with several immune and inflammatory diseases such as arthritis, influenza A virus infection, and lung inflammation. However, the role of FHL2 in macrophage differentiation and in the development of granuloma formation is unknown. Here, we show that expression of FHL2 is induced in mouse bone marrow derived macrophages (BMMs) following stimulation with M2 cytokines such as IL-4 and IL-10. FHL2-knockout (FHL2-KO) BMMs exhibit a proinflammatory M1 phenotype after LPS treatment and display a reduced anti-inflammatory M2 phenotype following IL-4 treatment. Furthermore, thioglycollate-induced migration of macrophages and B cells is enhanced in FHL2-KO mice. To evaluate the importance of FHL2 in the development of pulmonary granuloma formation, FHL2-KO mice were challenged with Schistosoma mansoni eggs. FHL2-KO mice show an enhanced number of granulomas and display decreased expression of Th2 markers and an exacerbated Th1 type of inflammation, characterized by enhanced expression of neutrophil markers and Th1 cytokines. Furthermore, the expression of barrier proteins is reduced in FHL2-KO lung compared to WT. Collectively, these data identify a previously unrecognized role for FHL2 in the pathogenesis of pulmonary granulomatous inflammation, partly through its effect on macrophage polarization, modulation of the Th1/Th2 balance and regulation of permeability in lung. Keywords: FHL2 granuloma Macrophages Permeability Schistosoma mansoniAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe helminth parasite, Schistosoma mansoni (Sm) causes some of the most debilitating and chronic diseases of mankind affecting Correspondence: Prof. Carlie J.M. de Vries e-mail: c.j.devries@amc.uva.nl more than 200 million people worldwide [1][2][3]. Schistosomiasis is a chronic disease that persists for years because of impaired ability to remove adult worms and the eggs that become trapped in the liver, lungs, and intestine as well as inadequate repair of local cellular damage [4]. Infection by Sm involves distinct phases, including an initial Th1 response involving IFN-γ followed by a stronger Th2 response, reflected by excessive expression of IL-4, IL-5, and IL-13, resulting in recruitment and activation of dendritic cells, C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3098-3106 Immunity to infection 3099 eosinophils, Th2 cells, and alternatively activated macrophages or M2 macrophages [3,5]. Macrophages are a heterogeneous population of immune cells playing a crucial role in the regulation of both innate and adaptive immune responses in inflammatory diseases, such as airway inflammation, inflammatory bowel disease, and atherosclerosis [6]. Macrophage polarization is a key event in multiple chronic pulmonary diseases including schistosomiasis and may help in regulation of tissue repair. Classical activation of macrophages (often indicated as M1) is induced by IFN-γ or LPS ...

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Deficiency in the LIM-only protein Fhl2 impairs skin wound healing

Cited by 78 publications

References 27 publications

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension

LIM‐only protein FHL2 regulates experimental pulmonary Schistosoma mansoni egg granuloma formation

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