Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis

Wilson, Cory; Mertens, Tinne; Shivshankar, Pooja; Bi, Weizen; Collum, Scott D.; Wareing, Nancy; Ko, Junsuk; Weng, Tingting; Naikawadi, Ram P.; Wolters, Paul J.; Maire, Pascal; Jyothula, Soma; Thandavarayan, Rajarajan Amirthalingam; Ren, Dewei; Elrod, Nathan D.; Wagner, Eric J.; Huang, Howard J.; Dickey, Burton F.; Ford, Heide L.; Karmouty‐Quintana, Harry

doi:10.1172/jci.insight.142984

Cited by 7 publications

(7 citation statements)

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“…Previously our group identified increased SIX1 in lung fibrosis(30) and SIX1 expression has been identified to be present in subcutaneous adipocytes particularly in those exhibiting aberrant function (60). As such we aimed to determine whether SIX1 was elevated in skin samples from SSc patients.…”

Section: Resultsmentioning

confidence: 98%

“…Our group and others identified sine oculis homeobox homolog 1 (SIX1) as a novel mediator in lung fibrosis promoting release of pro-fibrotic mediators by alveolar epithelial cells. (30)(31)(32) Further, SIX1 has also been implicated in asthmatic lung fibrosis (31,32) and in liver fibrosis defined by excessive myofibroblast activation and ECM deposition (33). Lung fibrosis is an important complication of SSc that is typically observed following onset of skin fibrosis and while epithelial and fibroblast based mechanisms are most highly studied, the contribution of the adipocyte to fibrotic process is not fully known.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

Wareing,

Mills,

Collum

et al. 2024

Preprint

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Background The cardinal feature of systemic sclerosis (SSc) is skin thickening and tightening. Targetable mechanisms for skin features remain elusive. Drugs successful in treating internal organ manifestations have failed efficacy in skin. Dermal white adipose tissue (DWAT) is amongst the understudied contributors to skin manifestations. This study proposes the role of sine oculis homeobox homolog 1 (SIX1), a gene previously unrecognized as a contributor to dermal lipoatrophy characteristic of early skin fibrosis in SSc. Methods Skin gene expression of SIX1 was analyzed in the GENISOS and PRESS SSc cohorts. Correlation analysis was performed with Spearman rank analysis. Novel mouse models were developed using the Cre-loxp system to knock out Six1 in all cells and mature adipocytes. Subcutaneous bleomycin was used to model early DWAT atrophy and dermal fibrosis characteristic of SSc. Findings SIX1 was upregulated in SSc skin, the expression of which correlates with adipose-associated genes and molecular pathways. Genetic deletion of Six1 in all cells in mice challenged with bleomycin abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage. Adipocyte specific Six1 deletion was able to attenuate the early increase in skin thickness, a hallmark of experimental skin fibrosis. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. Interpretation This work identifies SIX1 as an early marker of skin fibrosis in SSc. We also demonstrate a causative role of Six1 in skin fibrosis by promoting adipocyte loss and show that deletion of Six1 in adipocytes has the potential of impacting early disease progression.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

Wareing,

Mills,

Collum

et al. 2024

Preprint

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“…mRNA and protein of SIX1 and its transcriptional coactivators EYA1 and EYA2 are elevated in pulmonary fibrosis. The increased SIX1 here is a reparative reactivation on a basis of chronic alveolar damage -a wound repair triggered developmental program reactivation [55].…”

Section: Atramentioning

confidence: 84%

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

Kast,

Zaghloul,

Sardi

et al. 2023

Preprint

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Rhabdomyosarcoma is a cancer arising from arrested myogenic differentiation, seen mainly in children or adolescents. Metastatic rhabdomyosarcoma is often fatal even with aggressive cytotoxic chemotherapies, surgery, and irradiation. SALIQ is an acronym for a multidrug augmentation regimen designed as an adjunct to current rhabdomyosarcoma chemotherapies. SALIQ uses five common non-oncology drugs, repurposed from general medicine use, to promote malignant clone maturation and inhibit rhabdomyosarcoma growth. The five drugs are: the cholesterol lowering drug simvastatin, the acne medicine tretinoin (ATRA), the psychiatric drug lithium carbonate, the antifungal drug itraconazole, and the food supplement quercetin. All five drugs are in common use for non-cancer conditions, are cheap, have an eminently safe side effect profile, and all five have preclinical evidence and good rationale for inhibiting rhabdomyosarcoma growth.

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“…AP‐1 functions downstream of TCR and CD8 costimulatory receptor and mediates antigen‐specific T cell activation [45]. Combining the observation that ISO‐1 treatment inhibited the activity of MIF in CD8 + T cells and the notion that MIF has intracellular cell‐regulatory functions [46], we speculated that MIF inhibition might suppress antigen‐specific CD8 + T‐cell activation via downstream AP‐1, though the exact molecular mechanisms remain elusive.…”

Section: Discussionmentioning

confidence: 99%

MIF inhibition alleviates vitiligo progression by suppressing CD8⁺ T cell activation and proliferation

Chen

Guo

et al. 2023

The Journal of Pathology

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In vitiligo, autoreactive CD8+ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte‐specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remains ill‐defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8+ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, in vitro experiments indicated that MIF‐inhibition suppressed the activation and proliferation of CD8+ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8+ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8+ T cells derived from MIF‐inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8+ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.

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Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis

Cited by 7 publications

References 71 publications

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

MIF inhibition alleviates vitiligo progression by suppressing CD8⁺ T cell activation and proliferation

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Sine oculis homeobox homolog 1 plays a critical role in pulmonary fibrosis

Cited by 7 publications

References 71 publications

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

Deletion of adipocyte Sine Oculis Homeobox Homolog 1 prevents lipolysis and attenuates skin fibrosis

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

MIF inhibition alleviates vitiligo progression by suppressing CD8+ T cell activation and proliferation

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Product

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MIF inhibition alleviates vitiligo progression by suppressing CD8⁺ T cell activation and proliferation