Adipose tissue remodeling via TSLP-mediated IL-4/IL-13 signaling: Implications for atopic dermatitis and skin barrier

Atopic dermatitis (AD) is a chronic inflammatory disorder causing substantial physical, psychological, and socioeconomic burdens, with a notable prevalence in various regions. It manifests with symptoms such as pruritis, erythematous patches, crusting, scaling, fissuring, and lichenification, with lesion distribution varying between pediatric and adult populations. Research advancements have uncovered immune and skin barrier gene abnormalities, dysregulated immune responses, microbiome imbalances, and environmental influences contributing to AD pathophysiology. Distinct subtypes of AD have been identified across different regions and age groups, each characterized by unique cytokine profiles and cell activation patterns. Skin barrier dysfunction, driven by genetic and environmental factors, is central to AD development. Mutations in the filaggrin gene and deficiencies in structural proteins, lipids, and tight junction proteins compromise barrier function. Immune-mediated mechanisms, particularly cytokine signaling via Janus kinase signal transducer and activator of transcription (STAT) pathways, contribute to downregulation of skin barrier proteins, inhibition of keratinocyte differentiation, and reduction of antimicrobial peptide synthesis, ultimately increasing skin permeability. Key immune pathways and cytokines such as IL-4, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin (TSLP) have emerged as pivotal pathways (Fig 1). However, despite these advancements, AD remains a complex and heterogeneous condition, exhibiting variations across demographics such as age, genetic makeup, and immune response profiles. Such variability underscores the multifaceted nature of AD and presents a challenge in devising universally effective treatment strategies. Research efforts have focused on elucidating specific cytokines and signaling pathways implicated in AD pathogenesis. Of particular interest is TSLP, a crucial cytokine in promoting type 2 immune responses that is implicated in diseases such as asthma and AD (Fig 1). Initially known for B-cell growth support, TSLP has diverse functions, including cell maturation, proliferation, and recruitment, acting on various cells such as dendritic cells (DCs), T cells, mast cells, and eosinophils. TSLP is produced primarily by epithelial and stromal cells in organs such as the lungs, skin, and gastrointestinal tract, triggered by environmental factors such as mechanical stress, infections, and inflammatory cytokines. Its production is positively regulated by proinflammatory cytokines such as IL-4 and IL-13, whereas IFN-γ and IL-17 inhibit TSLP production. TSLP acts through a receptor complex involving TSLP receptor and IL-7 receptor α-chain (IL-7Rα), activating downstream signaling cascades and promoting differentiation of naive CD4+ T cells into proinflammatory TH2 cells. In AD, TSLP is highly expressed in lesions and contributes to disease severity and persistence. It induces TH2 cytokine release and IgE-mediated allergic responses, playing a pivotal role in AD pathogenesis. Involvement in promoting TH2 cell/TH17 cell polarization and modulating FcRγ-related receptors on monocytes underscores its significance in driving AD pathology. Meanwhile, periostin, a matricellular protein downstream of IL-4 and IL-13 signals, is also highly expressed in AD lesions. It exacerbates type 2 inflammation in AD and its pruritis by activating nuclear factor-κB in keratinocytes and inducing proinflammatory mediators such as TSLP.1Nunomura S. Uta D. Kitajima I. Nanri Y. Matsuda K. Ejiri N. et al.Periostin activates distinct modules of inflammation and itching downstream of the type 2 inflammation pathway.Cell Rep. 2023; 42111933Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Thus, understanding the function of TSLP offers insights into the mechanisms of AD and therapeutic strategies in relation to TSLP. However, previous studies on AD barrier dysfunction have focused primarily on keratinocyte lipid synthesis, with minimal attention given to lipids from sebaceous glands. Sebaceous glands, characterized as holocrine glands, are located on the skin surface, where gland cells disintegrate and secrete at the apex of the hair follicle (Fig 1).2Shi V.Y. Leo M. Hassoun L. Chahal D.S. Maibach H.I. Sivamani R.K. Role of sebaceous glands in inflammatory dermatoses.J Am Acad Dermatol. 2015; 73: 856-863Abstract Full Text Full Text PDF PubMed Google Scholar They are notably abundant on the face, back, and chest. Recent research has revealed that IL-4 and IL-13 can stimulate androgen production and induce lipid abnormalities in both mouse skin and human sebocytes.3Zhang C. Chinnappan M. Prestwood C.A. Edwards M. Artami M. Thompson B.M. et al.Interleukins 4 and 13 drive lipid abnormalities in skin cells through regulation of sex steroid hormone synthesis.Proc Natl Acad Sci U S A. 2021; 118e2100749118Crossref Scopus (27) Google Scholar Consequently, sebaceous glands play a crucial role in maintaining the skin barrier. In AD, lowered sebum content is often linked with reduced skin hydration, indicating an association between decreased sebaceous gland function and compromised skin barrier integrity.2Shi V.Y. Leo M. Hassoun L. Chahal D.S. Maibach H.I. Sivamani R.K. Role of sebaceous glands in inflammatory dermatoses.J Am Acad Dermatol. 2015; 73: 856-863Abstract Full Text Full Text PDF PubMed Google Scholar In a previous study, Choa et al found that T cells are the factor linking TSLP and sebum independently of other immune cells such as innate lymphoid cells, DCs, and B cells.4Choa R. Tohyama J. Wada S. Meng H. Hu J. Okumura M. et al.Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.Science. 2021; 373eabd2893Crossref PubMed Scopus (37) Google Scholar Therefore, in this issue of the Journal of Allergy and Clinical Immunology, Choa et al further investigated the mechanism underlying TSLP-mediated stimulation of sebum secretion and adipose loss, revealing the critical role of T-cell interactions and IL-4/IL-13 signaling pathways (Fig 1).5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar The study led by Choa et al5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar investigated the complex interplay between TSLP signaling and skin immune responses in orchestrating adipose loss and sebum secretion by using innovative single-cell RNA sequencing techniques. By inducing TSLP overexpression via utilization of mouse models injected with TSLP–adeno-associated virus serotype 8 and conducting single-cell RNA sequencing in conjunction with T-cell receptor (TCR) sequencing, the investigators revealed a diverse landscape of skin lymphocytes, notably emphasizing the involvement of T cells in mediating TSLP-driven effects. Intriguingly, TSLP treatment led to a distinct shift in the composition of skin lymphocytes, characterized by an increase in effector T cells and a reduction in other immune cell populations. Moreover, TCR sequencing unveiled considerable diversity in TCR repertoire among T cells from TSLP-treated mice, highlighting the importance of T-cell activation and migration in TSLP-induced responses. Importantly, unlike the studies of Choa et al,4Choa R. Tohyama J. Wada S. Meng H. Hu J. Okumura M. et al.Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.Science. 2021; 373eabd2893Crossref PubMed Scopus (37) Google Scholar,5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar previous studies have demonstrated that TSLP promotes TH2 cell differentiation by activating DCs rather than directly influencing TH2 cells in the skin.6Bell B.D. Kitajima M. Larson R.P. Stoklasek T.A. Dang K. Sakamoto K. et al.The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses.Nat Immunol. 2013; 14: 364-371Crossref PubMed Scopus (151) Google Scholar Although TSLP is known to play a significant role in skin type 2 inflammation mediated by DCs, the possibility remains that it may have direct effects on TH2 cells, thereby contributing to type 2 inflammation.7He R. Oyoshi M.K. Garibyan L. Kumar L. Ziegler S.F. Geha R.S. TSLP acts on infiltrating effector T cells to drive allergic skin inflammation.Proc Natl Acad Sci U S A. 2008; 105: 11875-11880Crossref PubMed Scopus (204) Google Scholar Further investigation into the role of TSLP in skin immunity, as exemplified by the study conducted by Choa et al,5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar is warranted. In their current study, Choa et al5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar explored the crucial role of IL-4 and IL-13 in TSLP-mediated adipose loss and sebum hypersecretion by using genetic knockout and adaptive transfer experiments, highlighting the necessity of IL-4/IL-13 signaling via the STAT6 pathway in driving these responses (Fig 1). Notably, IL-13 alone was found to be sufficient to induce adipose loss and sebum hypersecretion independently of TSLP signaling, shedding light on the downstream effector mechanisms in this cascade.5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar These experimental results support recent findings indicating dysregulation of the sebum lipidome in AD, implying a role for IL-4 and IL-13 in mediating lipid metabolism.8Yin H. Qiu Z. Zhu R. Wang S. Gu C. Yao X. et al.Dysregulated lipidome of sebum in patients with atopic dermatitis.Allergy. 2023; 78: 1524-1537Crossref PubMed Scopus (12) Google Scholar Lastly, Choa et al5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar investigated the use of a human sebocyte cell line to elucidate the direct impact of IL-4 and IL-13 on sebocyte function. They demonstrated that IL-4 and IL-13 stimulated sebocyte lipogenesis and proliferation, reflecting the observed phenotypic changes in vivo. Additionally, laser capture microdissection coupled with RNA sequencing of sebaceous glands unveiled dynamic transcriptional alterations associated with TSLP treatment, implicating dysregulated lipid metabolism and cell death pathways. This discovery establishes a connection between type 2 inflammation and the remodeling of sebaceous glands, offering novel insights into the role of sebaceous glands in barrier function alterations in AD (Fig 1). Galectin-12, a lipogenic factor expressed in sebocytes, indicates potential for further advancements in this field.9Lin F.J. Huang Y.H. Tsao C.H. Hsieh W.C. Lo Y.H. Zouboulis C.C. et al.Galectin-12 regulates immune responses in the skin through sebaceous glands.J Invest Dermatol. 2023; 143: 2120-2131.e7Abstract Full Text Full Text PDF Scopus (0) Google Scholar The findings of Choa et al5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar also provide important clinical implications. Previous studies have demonstrated that dupilumab, which inhibits IL-4/IL-13-signaling, enhances transepidermal water loss.10Berdyshev E. Goleva E. Bissonnette R. Bronova I. Bronoff A.S. Richers B.N. et al.Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis.Allergy. 2022; 77: 3388-3397Crossref PubMed Scopus (41) Google Scholar On the other hand, dysregulation of the sebum lipidome has been reported in patients with AD.8Yin H. Qiu Z. Zhu R. Wang S. Gu C. Yao X. et al.Dysregulated lipidome of sebum in patients with atopic dermatitis.Allergy. 2023; 78: 1524-1537Crossref PubMed Scopus (12) Google Scholar Therefore, when combined with these previous findings, the current study by Choa et al,5Choa R. Harris J.C. Yang E. Yokoyama Y. Okumura M. Kim M. et al.Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss.J Allergy Clin Immunol. 2024; 154 (xxx-xxx)Google Scholar which suggests that IL-4 and IL-13 modulate sebum secretion, implies that IL-4/IL-13 may indirectly regulate skin barrier function via sebum. Future studies could explore the effects of blocking IL-4/IL-13 signaling on adipose tissue in clinical settings. Disclosure of potential conflict of interest: The author declares that he has no relevant conflicts of interest. Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose lossJournal of Allergy and Clinical ImmunologyPreviewThe skin is a critical barrier surface that needs to sense and protect the host from the environment.1 One way the skin protects against environmental threats is through the production and secretion of a lipid-rich substance called sebum. Sebum is produced by sebaceous glands that lie within the mid-dermis and make up part of the pilosebaceous unit alongside hair follicles.2 Sebaceous gland lipids help repel water and prevent water loss, act as a delivery vehicle for secreted antimicrobial peptides,3,4 provide nutrients and differentiation signals for skin resident immune cells,5,6 regulate the skin microbiota composition,7,8 and have antibacterial and antifungal properties. Full-Text PDF