Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10

Background Atopic dermatitis (AD) is a T cell-mediated inflammatory skin disease, with T_H2 cells initiating acute flares. This inflamed skin is immediately colonized with Staphylococcus aureus, which provides potent Toll-like receptor (TLR) 2 ligands. However, the effect of TLR2 ligands on the development of T_H2-mediated AD inflammation remains unclear. Objective We investigated the progression of T_H2 cell-mediated dermatitis after TLR2 activation. Methods Using models for acute AD with T _H2 cells initiating cutaneous inflammation, we investigated the consequences of TLR2 activation. Dermatitis, as assessed by changes in ear skin thickness and histology, was analyzed in different BALB/c and C57BL/6 wild-type and knockout mouse strains, and immune profiling was carried out by using in vitro and ex vivo cytokine analyses. Results We show that T_H2 cell-mediated dermatitis is self-limiting and depends on IL-4. Activation of TLR2 converted the limited T_H2 dermatitis to chronic cutaneous inflammation. We demonstrate that the concerted activation of TLR2 and IL-4 receptor on dendritic cells is sufficient for this conversion. As an underlying mechanism, we found that the combinatorial sensing of the innate TLR2 ligands and the adaptive T_H2 cytokine IL-4 suppressed anti-inflammatory IL-10 and consequently led to the exacerbation and persistence of dermatitis. Conclusion Our data demonstrate that innate TLR2 signals convert transient T_H2 cell-mediated dermatitis into persistent inflammation, as seen in chronic human AD, through IL-4-mediated suppression of IL-10. For the first time, these data show how initial AD lesions convert to chronic inflammation and provide another rationale for targeting IL-4 in patients with AD, a therapeutic approach that is currently under development.