Highlights
- •Expression of β6 and β8 in human skin recapitulates expression in murine skin.
- •Skin from inflammatory conditions show increased integrin β6 expression.
- •Compared to benign nevi, melanomas show increased integrin β8 expression.
- •Increased integrin β8 expression may be a prognostic factor in melanoma.
Abstract
Background
Integrins avβ6 and avβ8 are expressed by keratinocytes and transactivate latent TGFβ.
In a murine model, integrin mediated activation of TGFβ has been shown to be critical
in maintaining skin homeostasis, specifically playing roles in epidermal retention
of Langerhans cells and resident memory cells T cells (Trm).
Objective
We examine expression of Integrins β6 and β8 in human skin, inflammatory skin disease,
benign nevi, and melanoma and hypothesize that integrin expression is dysregulated
in disease.
Methods
Using immunohistochemistry, we stained tissue from normal human skin (n = 8), psoriasis
(n = 6), atopic dermatitis (n = 6), lichen planus (n = 5), benign nevi (n = 24), and
melanoma (n = 25) with anti-integrin β6 and anti-integrin β8 to survey expression
pattern. We also performed a retrospective chart review in the melanoma cohort to
examine if integrin β6 and β8 expression was associated with increased Breslow depth
and worse prognostic staging.
Results
Here, we show that human keratinocytes express integrins β6 and β8, similar to murine
keratinocytes. We also found that inflammatory skin conditions have increased Integrin
β6, but not Integrin β8 expression. Furthermore, we identified that melanomas have
greatly increased expression of integrin β8 compared to nevi. Additionally, high expression
of integrin β8 was correlated with greater Breslow depth at diagnosis and with worse
prognostic staging.
Conclusion
These findings demonstrate that like murine keratinocytes, human keratinocytes express
integrin β6 and β8 under steady state conditions. Moreover, altered integrin expression
may participate in the development or maintenance of cutaneous inflammation as well
as tumor immune evasion.
Keywords
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References
- Integrins: bidirectional, allosteric signaling machines.Cell. 2002; 110: 673-687
- TGF-β activation and function in immunity.Annu. Rev. Immunol. 2014; 32: 51-82
- Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice.J. Cell Sci. 2009; 122: 227-232
- Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice.J. Cell Biol. 2007; 176: 787-793
- Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β.Nat. Immunol. 2016; 17: 414-421
- TNF-α and IL-1β do not induce langerhans cell migration by inhibiting TGFβ activation.JID Innov. 2021; 1100028
- Overexpression of the alphavbeta6 integrin in endometrial cancer.Appl. Immunohistochem. Mol. Morphol. 2008; 16: 543-547
- The roles of integrin αvβ6 in cancer.Cancer Lett. 2017; 403: 128-137
- αv-Integrin isoform expression in primary human tumors and brain metastases.Int. J. Cancer. 2013; 133: 2362-2371
- A tumor-specific mechanism of T(reg) enrichment mediated by the integrin αvβ8.Sci. Immunol. 2021; 6: 57
- Overexpression of integrin αv facilitates proliferation and invasion of oral squamous cell carcinoma cells via MEK/ERK signaling pathway that is activated by interaction of integrin αvβ8 with type Ⅰ collagen.Int. J. Oncol. 2014; 45: 1875-1882
- The role of integrins in TGFβ activation in the tumour stroma.Cell Tissue Res. 2016; 365: 657-673
- Epigenetic regulation of integrin β6 transcription induced by TGF-β1 in human oral squamous cell carcinoma cells.J. Cell. Biochem. 2018; 119: 4193-4204
- Interaction between oral squamous cell carcinoma cells and fibroblasts through TGF-β1 mediated by podoplanin.Exp. Cell Res. 2018; 369: 43-53
- Integrin αvβ8-expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells.JCI Insight. 2018; 3: 20
- Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin.Nat. Immunol. 2012; 13: 744-752
- Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J. Clin. 2017; 67: 472-492
- The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing.Cell Cycle. 2016; 15: 2077-2086
- Keratinocytes in Human Wounds Express αvβ6 Integrin.J. Investig. Dermatol. 1996; 106: 42-48
- Integrin alphanvbeta6 acts as a prognostic indicator in gastric carcinoma.Clin. Oncol. (R. Coll. Radiol.). 2008; 20: 61-66
- High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.Cancer Med. 2016; 5: 2000-2011
- Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival.J. Pathol. 2007; 212: 316-324
- alpha vbeta 6 Integrin promotes the invasion of morphoeic basal cell carcinoma through stromal modulation.Cancer Res. 2008; 68: 3295-3303
- Competition for active TGFβ cytokine allows for selective retention of antigen-specific tissue- resident memory T cells in the epidermal niche.Immunity. 2021; 54 (.e5): 84-98
Article info
Publication history
Published online: January 28, 2022
Accepted:
January 26,
2022
Received in revised form:
January 12,
2022
Received:
September 30,
2021
Identification
Copyright
© 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
