Antagonistic Effects of IL-4 on IL-17A-Mediated Enhancement of Epidermal Tight Junction Function

Abstract

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity.

Epicutaneous challenge with protease allergen requires its protease activity to recall TH2 and TH17/TH22 responses in mice pre-sensitized via distant skin

“…A T H 17 cytokine, IL-17A, decreases synthesis of tight junction proteins and degradation of filaggrin monomers (Yuki et al 2016), suggesting a vicious cycle between T H 2 and T H 17 sensitization and skin barrier dysfunction. Another study reported that IL-17A enhances the formation of tight junction proteins and barrier function (Brewer et al 2019).…”

A Spectrum of Skin Disease: How Staphylococcus aureus Colonization, Barrier Dysfunction, and Cytokines Shape the Skin

“…IL-17 is thought to have a number of protective roles in the skin, including enhancing production of antimicrobial peptides, such as lipocalin 2 and b-defensin, as well as neutrophil recruitment (Guttman-Yassky and Krueger, 2017). More recently, IL-17A has also been shown to enhance tight junction (TJ) barrier function in primary human keratinocytes (Brewer et al, 2019). Collectively, these actions likely contribute to the observation made by Sirobhushanam et al (2020) that none of their six subjects with PS were colonized with S. aureus.…”

“…Ustekinumab, a monoclonal antibody targeting IL-12 and IL-23 that is FDA-approved to treat PS, has also shown some benefit for the treatment of LE (van Vollenhoven et al, 2018). This might seem surprising based on its inhibition of the IL-17 pathway, which one might predict would further aggravate skin barrier dysfunction and promote S. aureus colonization in LE (Brewer et al, 2019). Although IL-17 has been shown to be modestly elevated in LE, there is not much evidence that this is relevant for LE pathogenesis (Martin et al, 2014).…”

Barrier defect in atopic dermatitis – possibilities and limits of basic skin therapy

“…Specifically, the enhancement of barrier function was measured by transepidermal electrical resistance (TEER), and tight junction formation was demonstrated by expression of the protein claudin-4. IL-4, as a key cytokine of allergic inflammation, again blocked these effects [ 18 ].…”