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Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease
Garrett J. Patrick, … , Nathan K. Archer, Lloyd S. Miller
Garrett J. Patrick, … , Nathan K. Archer, Lloyd S. Miller
Published March 1, 2021
Citation Information: J Clin Invest. 2021;131(5):e143334. https://doi.org/10.1172/JCI143334.
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Research Article Immunology Inflammation Article has an altmetric score of 15

Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease

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Abstract

IgE induced by type 2 immune responses in atopic dermatitis is implicated in the progression of atopic dermatitis to other allergic diseases, including food allergies, allergic rhinitis, and asthma. However, the keratinocyte-derived signals that promote IgE and ensuing allergic diseases remain unclear. Herein, in a mouse model of atopic dermatitis–like skin inflammation induced by epicutaneous Staphylococcus aureus exposure, keratinocyte release of IL‑36α along with IL-4 triggered B cell IgE class-switching, plasma cell differentiation, and increased serum IgE levels—all of which were abrogated in IL-36R–deficient mice or anti-IL‑36R–blocking antibody–treated mice. Moreover, skin allergen sensitization during S. aureus epicutaneous exposure-induced IL-36 responses was required for the development of allergen-specific lung inflammation. In translating these findings, elevated IL‑36 cytokines in human atopic dermatitis skin and in IL‑36 receptor antagonist–deficiency patients coincided with increased serum IgE levels. Collectively, keratinocyte-initiated IL‑36 responses represent a key mechanism and potential therapeutic target against allergic diseases.

Authors

Garrett J. Patrick, Haiyun Liu, Martin P. Alphonse, Dustin A. Dikeman, Christine Youn, Jack C. Otterson, Yu Wang, Advaitaa Ravipati, Momina Mazhar, George Denny, Roger V. Ortines, Emily Zhang, Robert J. Miller, Carly A. Dillen, Qi Liu, Sabrina J. Nolan, Kristine Nguyen, LeeAnn Marcello, Danh C. Do, Eric M. Wier, Yan Zhang, Gary Caviness, Alexander C. Klimowicz, Diane V. Mierz, Jay S. Fine, Guangping Sun, Raphaela Goldbach-Mansky, Alina I. Marusina, Alexander A. Merleev, Emanual Maverakis, Luis A. Garza, Joshua D. Milner, Peisong Gao, Meera Ramanujam, Ernest L. Raymond, Nathan K. Archer, Lloyd S. Miller

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Figure 3

IL-36R–induced serum IgE levels are dependent on CD4+ T cells and IL-4 in a mechanism independent of IL-36R–intrinsic signaling in CD4+ T cells.

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IL-36R–induced serum IgE levels are dependent on CD4+ T cells and IL-4 i...
(A–E) The S. aureus e.c. model was performed. (A) Mean disease score ± SEM and mean total serum IgE ± SEM after treating WT mice with anti-CD4 (to deplete CD4+ T cells) or isotype control mAb (n = 5/group). (B) βδ–/– mice (deficient in αβ and γδ T cells) with or without adoptive transfer of CD4+ or γδ T cells from dLNs of naive WT mice (n = 3–5/group). (C) WT and CD4-cre × IL-36Rfl/fl mice (IL-36R deleted in CD4+ cells) (n = 5/group). (D) Mice treated with anti-IL-4 or isotype control mAb (n = 5/group). (E) Representative flow plots and mean percentage of IL-4+ T cells (CD4+ versus TCRγδ+) ± SEM from day 0, 7, and 10 dLNs of WT mice (n = 4–5/group). ‡P < 0.001 between indicated groups, as calculated by a 2-tailed Student’s t test (A and C–E) or 1-way ANOVA with Tukey correction for multiple comparisons (B). Results are representative of 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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