The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin

Sophie Ward; Greg Crawford; Buang Norzawani; Christina Malactou; Emma Dutton; Isabella Withnell; Kevin J. Woollard; Catherine Harwood; Henry J. McSorley; Christoph Ziegenhain; Adrian Lärkeryd; Anguraj Sadanandam; Jessica Strid

doi:10.1016/j.celrep.2025.115837

The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin

Sophie Ward
, Greg Crawford
, Buang Norzawani
, Christina Malactou
, Emma Dutton
, Isabella Withnell
, Kevin J. Woollard
, Catherine Harwood
, Henry J. McSorley
, Christoph Ziegenhain
, Adrian Lärkeryd
, Anguraj Sadanandam
, Jessica Strid

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

44 Downloads (Pure)

Abstract

Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33⁺ epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.

Original language	English
Article number	115837
Journal	Cell Reports
Volume	44
Issue number	6
Early online date	14 Jun 2025
DOIs	https://doi.org/10.1016/j.celrep.2025.115837
Publication status	Published - 24 Jun 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

cancer
CP: Cancer
CP: Immunology
cSCC
IL-33
immune-surveillance
inflammation
skin
ST2 receptor
Treg
type 2 immunity

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2025.115837Licence: CC BY

Final Published VersionFinal published version, 54.3 MBLicence: CC BY

Cite this

Ward, S., Crawford, G., Norzawani, B., Malactou, C., Dutton, E., Withnell, I., Woollard, K. J., Harwood, C., McSorley, H. J., Ziegenhain, C., Lärkeryd, A., Sadanandam, A., & Strid, J. (2025). The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin. Cell Reports, 44(6), Article 115837. https://doi.org/10.1016/j.celrep.2025.115837

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title = "The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin",

abstract = "Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33+ epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.",

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author = "Sophie Ward and Greg Crawford and Buang Norzawani and Christina Malactou and Emma Dutton and Isabella Withnell and Woollard, \{Kevin J.\} and Catherine Harwood and McSorley, \{Henry J.\} and Christoph Ziegenhain and Adrian L{\"a}rkeryd and Anguraj Sadanandam and Jessica Strid",

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AU - Crawford, Greg

AU - Norzawani, Buang

AU - Malactou, Christina

AU - Dutton, Emma

AU - Withnell, Isabella

AU - Woollard, Kevin J.

AU - Harwood, Catherine

AU - McSorley, Henry J.

AU - Ziegenhain, Christoph

AU - Lärkeryd, Adrian

AU - Sadanandam, Anguraj

AU - Strid, Jessica

PY - 2025/6/24

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N2 - Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33+ epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.

AB - Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33+ epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.

KW - cancer

KW - CP: Cancer

KW - CP: Immunology

KW - cSCC

KW - IL-33

KW - immune-surveillance

KW - inflammation

KW - skin

KW - ST2 receptor

KW - Treg

KW - type 2 immunity

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M3 - Article

C2 - 40517383

AN - SCOPUS:105007871308

SN - 2639-1856

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 115837

ER -

The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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