IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote Saureus clearance in antigen sensitized mouse skin

• Published in: Journal of allergy and clinical immunology 2023-10, Vol.152 (4), p.907-915
• Main Authors: Leyva-Castillo, Juan-Manuel, McGurk, Alex, Strakosha, Maria, Vega-Mendoza, Daniela, Smith, Sophia E.M., Stafstrom, Kelsey, Elkins, Megan, Chou, Janet, Wang, Yui-Hsi, Geha, Raif S.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents; Antigens; Atopic dermatitis; Dermatitis, Atopic - drug therapy; IL-17A; IL-4Rα; Inflammation; Interleukin-17 - genetics; Mice; Mice, Inbred BALB C; Ovalbumin; Receptors, Interleukin-4; Saureus; Skin; type 2 cytokines
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2023.05.025

[Display omitted] Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor α (IL-4Rα) blockade is beneficial in atopic dermatitis and reduces Saureus skin colonization through unknown mechanisms. The cytokine IL-17A restrains Saureus growth. This study sought to examine the effect of IL-4Rα blockade on Saureus colonization at sites of allergic skin inflammation in mice and determine the mechanism involved. BALB/c mice were epicutaneously sensitized with ovalbumin (OVA). Immediately after, PSVue 794-labeled S aureus strain SF8300 or saline was applied and a single dose of anti-IL-4Rα blocking antibody, a mixture of anti-IL-4Rα and anti-IL-17A blocking antibodies, or IgG isotype controls were administered intradermally. Saureus load was assessed 2 days later by in vivo imaging and enumeration of colony forming units. Skin cellular infiltration was examined by flow cytometry and gene expression by quantitative PCR and transcriptome analysis. IL-4Rα blockade decreased allergic skin inflammation in OVA-sensitized skin, as well as in OVA-sensitized and Saureus–exposed skin, evidenced by significantly decreased epidermal thickening and reduced dermal infiltration by eosinophils and mast cells. This was accompanied by increased cutaneous expression of Il17a and IL-17A–driven antimicrobial genes with no change in Il4 and Il13 expression. IL-4Rα blockade significantly decreased Saureus load in OVA-sensitized and S aureus–exposed skin. IL-17A blockade reversed the beneficial effect of IL-4Rα blockade on Saureus clearance and reduced the cutaneous expression of IL-17A–driven antimicrobial genes. IL-4Rα blockade promotes Saureus clearance from sites of allergic skin inflammation in part by enhancing IL-17A expression.