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

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 2

IL-36 responses are dependent on the anatomical localization of S. aureus challenge.

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IL-36 responses are dependent on the anatomical localization of S. aureu...
The S. aureus i.d. model (A–F) or e.c. model (E and F) was performed in WT and IL-36R–/– mice. (A) Timeline of S. aureus i.d. model. (B) Mean total lesion size (cm2) ± SEM and mean in vivo bacterial bioluminescence imaging signals (total flux; photons/s) ± SEM (n = 5/group). (C) Mean serum IgE (ng/mL) (n = 4–5/group) and (D) IgG1 and IgG2a levels (ng/mL) ± SEM (n = 4/group). (E) Mean mRNA levels (AU) ± SEM of transcripts for IL-36α ± SEM (n = 4–9/group). (F) Representative immunofluorescence microscopy sections on days 0 and 10 labeled with anti-IL‑36α (green) and DAPI (blue). Scale bars: 100 μm; dashed line indicates dermoepidermal junction. †P < 0.01 between indicated groups, as calculated by 2-way ANOVA. Results are representative of 2 independent experiments.