Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss - 23/01/24

Doi : 10.1016/j.jaci.2023.11.923

Ruth Choa, MD, PhD ^a, Jordan C. Harris, BS ^a, EnJun Yang, PhD ^b, Yuichi Yokoyama, MD, PhD ^a, Mariko Okumura, BS ^a, MinJu Kim, BS ^a, Jerrick To, PhD ^a, Meng Lou, BS ^a, Amanda Nelson, PhD ^c, Taku Kambayashi, MD, PhD ^a,^⁎
^a Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
^b Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A∗STAR), Singapore
^c Department of Dermatology, Penn State Milton S. Hershey Medical Center, Hershey, Pa

^∗Corresponding author: Taku Kambayashi, MD, PhD, 288 JMB, 3620 Hamilton Walk, Philadelphia, PA 19104.288 JMB3620 Hamilton WalkPhiladelphiaPA19104

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Graphical abstract

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Abstract

Background

The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown.

Objectives

This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss.

Methods

RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro.

Results

This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro.

Conclusions

This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss.

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Key words : Sebaceous gland, sebum, T cells, IL-4, IL-13, TSLP, adipose loss

Abbreviations used : AAV, DEGs, DMEM, eWAT, GO, GSEA, ILC, LCM, TCR