Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis

HogenEsch, Harm; Sola, Mario; Stearns, Timothy M.; Silva, Kathleen A.; Kennedy, Victoria E.; Sundberg, John P.

doi:10.1016/j.yexmp.2016.05.015

Cited by 10 publications

(7 citation statements)

References 41 publications

(54 reference statements)

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“…Eosinophils were also present in the epidermis and occasionally formed intracorneal and subcorneal pustules. There were increased numbers of cross-sections of small blood vessels in the dermis as found in the spontaneous mutants [56]. The dermis of older mice had an increase of collagen deposition (fibrosis).…”

Section: Plos Onementioning

confidence: 83%

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

et al. 2020

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Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/provides a new model to study atopic dermatitis.

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Section: Plos Onementioning

confidence: 83%

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

et al. 2020

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“…Increased permeability leads to increased migration of tumor cells through endothelium and into the bloodstream, which is a common route for metastases to form (28). Expression of vascular endothelial growth factor A messenger RNA is increased in skin lesions of Sharpin cpdm mice, where the number of blood vessels is increased (29). In addition, we observed that tumor uptake of VAP-1-targeting 68 Ga-DOTA-Siglec-9 was significantly higher in Sharpin cpdm than in wt mice.…”

Section: Discussionmentioning

confidence: 72%

⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

et al. 2019

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Shank-associated RH domain-interacting protein (SHARPIN) is a cytosolic protein that plays a key role in activation of nuclear factor κ-light-chain enhancer of activated B cells and regulation of inflammation. Furthermore, SHARPIN controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice. Arginyl-glycyl-aspartic acid (RGD), a cell adhesion tripeptide motif, is an integrin recognition sequence that facilitates PET imaging of integrin upregulation during tumor angiogenesis. We hypothesized that increased integrin activity due to loss of SHARPIN protein would affect the uptake of α v β 3-selective cyclic, dimeric peptide 68 Ga-DOTA-E[c(RGDfK)] 2 , where E[c(RGDfk)] 2 5 glutamic acid-[cyclo(arginyl-glycylaspartic acid-D-phenylalanine-lysine)], both in several tissue types and in the tumor microenvironment. To test this hypothesis, we used RGDbased in vivo PET imaging to evaluate wild-type (wt) and SHARPIN-deficient mice (Sharpin cpdm , where cpdm 5 chronic proliferative dermatitis in mice) with and without melanoma tumor allografts. Methods: Sharpin cpdm mice with spontaneous null mutation in the Sharpin gene and their wt littermates with or without B16-F10-luc melanoma tumors were studied by in vivo imaging and ex vivo measurements with cyclic-RGD peptide 68 Ga-DOTA-E[c(RGDfK)] 2. After the last 68 Ga-DOTA-E[c(RGDfK)] 2 peptide PET/CT, tumors were cut into cryosections for autoradiography, histology, and immunohistochemistry. Results: The ex vivo uptake of 68 Ga-DOTA-E[c(RGDfK)] 2 in the mouse skin and tumor was significantly higher in Sharpin cpdm mice than in wt mice. B16-F10-luc tumors were detected 4 d after inoculation, without differences in volume or blood flow between the mouse strains. PET imaging with 68 Ga-DOTA-E[c(RGDfK)] 2 peptide at day 10 after inoculation revealed significantly higher uptake in the tumors transplanted into Sharpin cpdm mice than in wt mice. Furthermore, tumor vascularization was increased in the Sharpin cpdm mice. Conclusion: Sharpin cpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment.

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“…5 Sharpincpdm mice developed epidermal hyperplasia and inflammation with increased rates of cell death in the skin, suggesting that SHARPIN may be involved in cell proliferation, apoptosis and inflammatory responses. 10,11 SHARPIN is also required to produce effective regulatory T cells in the body. 12 The absence of an interaction between SHARPIN and the truncated nuclear factor kappa B essential modulator protein has been reported as a possible pathogenic mechanism in incontinentia pigmenti.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of SHANK‐associated RH domain‐interacting protein elevates interleukin‐33 expression by stimulating the Janus kinase 2/signal transducer and activator of transcription signalling pathway in HaCaT cells

et al. 2021

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Summary Background Atopic dermatitis (AD) is a chronic inflammatory skin disease in which T‐helper type 2 (Th2) immune responses are dominant. SH3 and multiple ankyrin repeat domains (SHANK)‐associated RH domain‐interacting protein (SHARPIN) is expressed at low levels in AD, resulting in the upregulation of the signal transducer and activator of transcription (STAT)3 protein and the Th2 cytokine, interleukin (IL)‐33. However, the roles of SHARPIN in AD are not yet fully elucidated. Aim To evaluate the signalling interactions of SHARPIN and IL‐33 in order to improve understanding of AD pathogenesis. Methods Western blotting was used to detect the Janus kinase (JAK)/STAT signalling proteins and IL‐33 protein in HaCaT cells to determine the key proteins mediating the interaction between SHARPIN and IL‐33. The findings were validated by immunofluorescence and immunohistochemical staining. Chromatin immunoprecipitation assays were used to evaluate the activity of STAT3 at the IL‐33 promoter. Results We found that phosphorylated (p)JAK2 and pSTAT3 were upregulated in SHARPIN‐knockdown HaCaT cells. Subsequent chromatin immunoprecipitation assays revealed that STAT3 binds to the IL‐33 promoter to mediate IL‐33 expression. Moreover, SHARPIN‐mediated expression of IL‐33 was reduced after treatment of HaCaT cells with the JAK/STAT inhibitor ruxolitinib. STAT3 and IL‐33 expression levels were higher in AD skin lesion tissues than in normal skin tissues. Conclusion These findings suggest that SHARPIN modulates inflammation in HaCaT cells by inhibiting JAK/STAT signalling, supporting the application of SHARPIN as a potential therapeutic target for AD.

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Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis

Cited by 10 publications

References 41 publications

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

Downregulation of SHANK‐associated RH domain‐interacting protein elevates interleukin‐33 expression by stimulating the Janus kinase 2/signal transducer and activator of transcription signalling pathway in HaCaT cells

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Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis

Cited by 10 publications

References 41 publications

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

68Ga-DOTA-E[c(RGDfK)]2 PET Imaging of SHARPIN-Regulated Integrin Activity in Mice

Downregulation of SHANK‐associated RH domain‐interacting protein elevates interleukin‐33 expression by stimulating the Janus kinase 2/signal transducer and activator of transcription signalling pathway in HaCaT cells

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⁶⁸Ga-DOTA-E[c(RGDfK)]₂ PET Imaging of SHARPIN-Regulated Integrin Activity in Mice