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1.
Nat Commun ; 13(1): 4703, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36050303

RESUMO

Atopic diseases, including atopic dermatitis (AD) and asthma, affect a large proportion of the population, with increasing prevalence worldwide. AD often precedes the development of asthma, known as the atopic march. Allergen sensitization developed through the barrier-defective skin of AD has been recognized to be a critical step leading to asthma, in which thymic stromal lymphopoietin (TSLP) was previously shown to be critical. In this study, using a laser-assistant microporation system to disrupt targeted skin layers for generating micropores at a precise anatomic depth of mouse skin, we model allergen exposure superficially or deeply in the skin, leading to epicutaneous sensitization or dermacutaneous sensitization that is associated with a different cytokine microenvironment. Our work shows a differential requirement for TSLP in these two contexts, and identifies an important function for IL-1ß, which is independent of TSLP, in promoting allergen sensitization and subsequent allergic asthma.


Assuntos
Asma , Citocinas , Dermatite Atópica , Interleucina-1beta , Alérgenos , Animais , Asma/complicações , Citocinas/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Pele , Linfopoietina do Estroma do Timo
2.
JCI Insight ; 7(21)2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36107619

RESUMO

Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Camundongos , Animais , Microambiente Tumoral , Melanoma/genética , Melanoma/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Citocinas/metabolismo , Queratinócitos/metabolismo , Linfopoietina do Estroma do Timo , Melanoma Maligno Cutâneo
3.
J Allergy Clin Immunol ; 147(5): 1778-1794, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33068561

RESUMO

BACKGROUND: Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TH2 has been believed to play a crucial role in cellular and humoral response in AD, but accumulating evidence has shown that follicular helper T cell (TFH), a critical player in humoral immunity, is associated with disease severity and plays an important role in AD pathogenesis. OBJECTIVES: This study aimed at investigating how TFHs are generated during the pathogenesis of AD, particularly what is the role of keratinocyte-derived cytokine TSLP and Langerhans cells (LCs). METHODS: Two experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization. RESULTS: This study demonstrated that the development of TFHs and germinal center (GC) response were crucially dependent on TSLP in both the MC903 model and the OVA sensitization model. Moreover, we found that LCs promoted TFH differentiation and GC response in the MC903 model, and the depletion of Langerin+ dendritic cells (DCs) or selective depletion of LCs diminished the TFH/GC response. By contrast, in the model with OVA sensitization, LCs inhibited TFH/GC response and suppressed TH2 skin inflammation and the subsequent asthma. Transcriptomic analysis of Langerin+ and Langerin- migratory DCs revealed that Langerin+ DCs became activated in the MC903 model, whereas these cells remained inactivated in OVA sensitization model. CONCLUSIONS: Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.


Assuntos
Citocinas/imunologia , Dermatite Atópica/imunologia , Células de Langerhans/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Alérgenos/imunologia , Animais , Calcitriol/análogos & derivados , Calcitriol/farmacologia , Diferenciação Celular , Fármacos Dermatológicos/farmacologia , Perfilação da Expressão Gênica , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/imunologia , Linfopoietina do Estroma do Timo
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