Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease
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
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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Research Article Immunology Inflammation

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 4

Antibody blockade of IL-36R inhibits skin inflammation and increased serum IgE levels in mice.

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Antibody blockade of IL-36R inhibits skin inflammation and increased ser...
(A–C) The S. aureus e.c. model was performed in WT mice treated with anti-IL-36R or isotype control mAb. (A) Representative skin photographs and mean disease score ± SEM (n = 5/group). (B) Representative histology (H&E stain; scale bars: 100 μm) and mean epidermal thickness (μm) ± SEM (n = 5/group). (C) Mean serum IgE (ng/mL) ± SEM (n = 10/group). (D–F) Healthy HCs and patients with AD were evaluated for: (D) mean serum IL-36α and IL-36γ protein levels (pg/mL) ± SEM (n = 14–29/group); (E) mean total serum IgE (IU/mL) ± SEM (n = 14–29/group); and (F) representative human skin mRNA expression of Il36α and Il36γ by in situ hybridization (ISH). Scale bars: 100 μm. *P < 0.05, †P < 0.01, ‡P < 0.001 between indicated groups, as calculated by a 2-tailed Student’s t test. Results are representative of 2 independent experiments.