Cellular mechanisms and effects of IL-4 receptor blockade in experimental conjunctivitis evoked by skin inflammation
Hongwei Han, Sheila Cummings, Kai-Ting C. Shade, Jennifer Johnson, George Qian, Joseph Gans, Srinivas Shankara, Javier Escobedo, Erik Zarazinski, Renee Bodinizzo, Dinesh Bangari, Paul Bryce, Alexandra Hicks
Hongwei Han, Sheila Cummings, Kai-Ting C. Shade, Jennifer Johnson, George Qian, Joseph Gans, Srinivas Shankara, Javier Escobedo, Erik Zarazinski, Renee Bodinizzo, Dinesh Bangari, Paul Bryce, Alexandra Hicks
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Research Article Dermatology Immunology

Cellular mechanisms and effects of IL-4 receptor blockade in experimental conjunctivitis evoked by skin inflammation

Abstract

Ocular surface diseases, including conjunctivitis, are recognized as common comorbidities in atopic dermatitis (AD) and occur at an increased frequency in patients with AD treated with biologics targeting IL-4 receptor α (IL-4Rα) or IL-13. However, the inflammatory mechanisms underlying this pathology are unknown. Here, we developed a potentially novel mouse model of skin inflammation–evoked conjunctivitis and showed that it is dependent on CD4+ T cells and basophils. Blockade of IL-4Rα partially attenuated conjunctivitis development, downregulated basophil activation, and led to a reduction in expression of genes related to type 2 cytokine responses. Together, these data suggest that an IL-4Rα/basophil axis plays a role in the development of murine allergic conjunctivitis. Interestingly, we found a significant augmentation of a number of genes that encode tear proteins and enzymes in anti–IL-4Rα–treated mice, and it may underlie the partial efficacy in this model and may represent candidate mediators of the increased frequency of conjunctivitis following dupilumab in patients with AD.

Authors

Hongwei Han, Sheila Cummings, Kai-Ting C. Shade, Jennifer Johnson, George Qian, Joseph Gans, Srinivas Shankara, Javier Escobedo, Erik Zarazinski, Renee Bodinizzo, Dinesh Bangari, Paul Bryce, Alexandra Hicks

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Figure 3

Basophils exhibit a distinct phenotype in AD-associated conjunctivitis.

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Basophils exhibit a distinct phenotype in AD-associated conjunctivitis. ...
(A) Representative flow cytometry plots and frequency of NTNB (CD3e−CD19−) CD49b+FcεRIα/IgE+ blood basophils in mice on day 24 of the conjunctivitis model. Data depicted are from 1 experiment (n = 5–10) and are representative of 2 independent replicates. *P < 0.05 by 1-way ANOVA with Tukey’s post hoc test. (B) FcεRIα/IgE expression measured by MFI on blood basophils in mice on day 24 of the conjunctivitis model. Data depicted are from 1 experiment (n = 5–10) and are representative of 2 independent replicates. (C) IHC staining performed on conjunctival tissue sections at day 24 with Ab against mMCP-8 (specific for basophils). Upper, MC903 + OVA/PBS; lower, MC903 + OVA/OVA. Scale bar: 100 μm. (D) Basophil IHC scores. Data are from 2 pooled experiments (n = 10). (E) Heatmap of basophil signature genes. (F) Heatmap of chemokine and receptor signature genes. The color gradient in E and F represents fold-change values; OVA-challenged samples were compared with PBS-challenged samples (n = 4–5). (G) Mcpt1 transcripts in conjunctival tissues (n = 4–5). (H) mMCP-1 in serum. Data depicted in B, D, G, and H are from 1 experiment (n = 10) and are representative of 2 independent replicates. **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired Student’s t test. NTNB, non-T non-B.