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

Background: Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor a (IL-4Ra) blockade is beneficial in atopic dermatitis and reduces S aureus skin colonization through unknown mechanisms. The cytokine IL -17A restrains S aureus growth.Objectives: This study sought to examine the effect of IL-4Ra blockade on S aureus colonization at sites of allergic skin inflammation in mice and determine the mechanism involved.Methods: 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-4Ra blocking antibody, a mixture of anti-IL-4Ra and anti-IL-17A blocking antibodies, or IgG isotype controls were administered intradermally. S aureus 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.Results: IL-4Ra blockade decreased allergic skin inflammation in OVA-sensitized skin, as well as in OVA-sensitized and S aureus-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-4Ra blockade significantly decreased S aureus load in OVA-sensitized and S aureus-exposed skin. IL-17A blockade reversed the beneficial effect of IL-4Ra blockade on S aureus clearance and reduced the cutaneous expression of IL-17A-driven antimicrobial genes.Conclusions: IL-4Ra blockade promotes S aureus clearance from sites of allergic skin inflammation in part by enhancing IL-17A expression. (J Allergy Clin Immunol 2023;152:907-15.)

Automated summary

IL-4Ra blockade reduces allergic skin inflammation and promotes the clearance of S aureus strain SF8300 from sites of allergic skin inflammation by enhancing IL-17A expression.