FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis

Wixler, Viktor; Cromme, C; Retser, Eugen; Meyer, Lars; Smyth, Neil; Mühlenberg, Katja; Korb-Pap, Adelheid; Koers-Wunrau, Christina; Sotsios, Yannis; Bassel‐Duby, Rhonda; Baeten, Dominique; Tak, Paul P.; Niederreiter, Birgit; Redlich, Kurt; Bertrand, Jessica; Skryabin, Boris V.; Ludwig, Stephan; Pap, Thomas

doi:10.1136/annrheumdis-2013-205061

Cited by 12 publications

(33 citation statements)

References 22 publications

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“…Accordingly, increased levels of S100a9 and Tnfsf11 (RANKL) mRNA, which commonly accompany keratinocyte activation and psoriatic alterations, as well as fibronectin ( Fn ), tenascin C ( Tnc ), and different matrix metalloproteases (MMPs), which accompany inflammation and tissue injury, were detected. Recently, we reported that chronic inflammation induced by long‐term expression of TNF or IL‐1 leads to down‐regulation of the tissue‐damage‐resolving protein FHL2 . Expression of Flh2 was also significantly down‐regulated in the skin of ihTNFtg mice after prolonged induction of TNF (Figure C).…”

Section: Resultsmentioning

confidence: 83%

Macrophage‐mediated psoriasis can be suppressed by regulatory T lymphocytes

Dantas¹,

Masemann²,

Schied³

et al. 2016

The Journal of Pathology

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We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops psoriasis-like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro-inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF-mediated psoriasis, ihTNFtg mice were crossbred into RAG1 mice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1 or wild-type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild-type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3-positive cells into RAG1 or wild-type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro-inflammatory activity of macrophages, which are the major immune effector cells in hTNF-mediated psoriasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Resultsmentioning

confidence: 83%

Macrophage‐mediated psoriasis can be suppressed by regulatory T lymphocytes

Dantas¹,

Masemann²,

Schied³

et al. 2016

The Journal of Pathology

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“…In recombinant human TNF-a-expressing transgenic mice that develop a severe form of rheumatoid arthritis within the first 10 wk after birth (29), FHL2 levels increased during early phases of rheumatoid arthritis development and decreased later on when the disease entered the chronic phase. Here, synovial fibroblasts and chondrocytes showed the highest expression (30,31). Also, during psoriasis and inflammatory bowel disease, FHL2 was significantly down-regulated in later stages of disease progression (30, 32 and unpublished results).…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 78%

“…These facts indicate that FHL2 is up-regulated during active tissue regeneration steps and that the failure of tissue repair and the development of chronic wounds or diseases always accompanies its suppression (9,25,27,30,31). These data further imply that deficiency of FHL2 should impair wound healing and foster development of chronic diseases.…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 89%

“…It is noteworthy that FHL2 might support tumor growth and metastasis, both directly being overexpressed in tumor cells and indirectly when it is overexpressed in tumorassociated stroma cells (2,10,26,85,86). To the contrary, sustained down-regulation of the FHL2 protein supports MMP expression and transition of wounds into chronic forms (30,31,42). FHL2 is involved in different steps of the wound-healing process, supporting tissue repair and coordinating inflammation.…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 99%

“…Furthermore, FHL2-KO mice seem to have a reduced threshold for development of several chronic diseases. It was reported that loss of the LIM-only protein FHL2 encouraged the development of corneal angiogenesis, hypertrophic cardiomyopathy (38), osteopenia (37), fibrosis (25,39,40), arthritis (30,31), psoriasis (30), and gliosis in the adult brain (41).…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 99%

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The role of FHL2 in wound healing and inflammation

Wixler

2019

FASEB j.

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The 4‐and‐a‐half LIM domain protein 2 (FHL2) is a multifunctional adaptor protein that can interact with cell surface receptors, cytosolic adaptor and structural proteins, kinases, and nuclear transcription factors. It is involved in numerous functional activities, including the epithelial‐mesenchymal transition, cell proliferation, apoptosis, adhesion, migration, structural stability, and gene expression. Despite this, FHL2‐knockout (KO) mice are viable and fertile with no obvious abnormalities, rather suggesting a high capacity for fine‐tuning adjustment and functional redundancy of FHL2. Indeed, challenging FHL2‐KO cells or mice provided numerous evidences for the great functional significance of FHL2. In recent years, several reviews have been published describing the high capacity of FHL2 to bind diverse proteins as well as the versatile functions of FHL2, emphasizing in particular its role in cardiovascular diseases and carcinogenesis. Here, we view the function of FHL2 from a different perspective. We summarize the published data demonstrating the impact of FHL2 on wound healing and inflammation. FHL2 seems to be involved in numerous steps of these extremely complex and multidirectional but tightly regulated tissue remodeling processes, supporting tissue repair and coordinating inflammation. Deficiency of FHL2 not only slows down ongoing wound healing but also often turns it into a chronic condition.—Wixler, V. The role of FHL2 in wound healing and inflammation. FASEB J. 33, 7799–7809 (2019). http://www.fasebj.org

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Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

Bhattaram

Muschler

Wixler

et al. 2018

Arthritis & Rheumatology

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Objectives Fibroblast-like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer-like and aggressively contribute to joint degeneration in inflammatory arthritis. Here we asked whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions. Methods We inactivated the SOXC genes in FLS of adult mice and studied consequences on joint homeostasis and tumor necrosis factor-alpha (TNFα)-induced arthritis. We used primary cells and synovial biopsies from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins. Results Postnatal inactivation of the SOXC genes had no major consequence on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNFα. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNFα on FLS aggressiveness, including increased cell survival and migration. SOXC RNA levels were unchanged by TNFα and other pro-inflammatory cytokines, but their proteins were strongly stabilized and able to potentiate the TNFα-induced upregulation of genes involved in FLS transformation. Substantiating the human disease relevance of these findings, the SOXC protein, but not RNA levels, were significantly higher in inflamed than non-inflamed synovium from arthritic patients. Conclusion SOXC proteins are targets and pivotal mediators of pro-inflammatory cytokines during FLS transformation in arthritic diseases. Their targeting could thus improve current strategies to treat these and possibly other inflammatory diseases.

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FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis

Abstract: These data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt.

Cited by 12 publications

References 22 publications

Macrophage‐mediated psoriasis can be suppressed by regulatory T lymphocytes

Macrophage‐mediated psoriasis can be suppressed by regulatory T lymphocytes

The role of FHL2 in wound healing and inflammation

Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

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