Juan Manuel Leyva-Castillo

IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

Geha and collaborators show that IL-23 released by keratinocytes in response to TLR4 ligands stimulates skin DCs to produce IL-23, driving CD4 T cell IL-22 secretion, which causes epidermal thickening.

Counterregulation between thymic stromal lymphopoietin- and IL-23-driven immune axes shapes skin inflammation in mice with epidermal barrier defects.

BACKGROUND Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood. OBJECTIVE We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier. METHODS We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes. RESULTS We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation. CONCLUSION The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD.

RORα-expressing T regulatory cells restrain allergic skin inflammation

Skin-resident T regulatory cells restrain cutaneous allergic inflammation by type 2 innate lymphoid cells. Curbing ILC2 enthusiasm Atopic dermatitis is an allergic disease driven by type 2 immune responses in the skin. Using mouse models of dermatitis, Malhotra et al. have identified tumor necrosis factor (TNF) family cytokine, TNF ligand–related molecule 1 (TL1A), and its receptor death receptor 3 (DR3) as being critical in regulating cross-talk between skin-resident T regulatory cells (Tregs) and type 2 innate lymphoid cells (ILC2) that drive skin inflammation. They report that retinoid-related orphan receptor α (RORα) drives expression of DR3 in Tregs and that, upon deletion of RORα, skin-resident Tregs are unable to sequester TL1A that drives effector functions of ILC2s. The studies open up the possibility of targeting the TL1A-DR3 in the context of dermatitis and other skin allergies. Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (Tregs) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH2 cells. Expression of RORα in skin-resident Tregs suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand–related molecule 1 (TL1A), which promotes Treg functions. DR3 is expressed on both ILC2s and skin-resident Tregs. Upon deletion of RORα in skin-resident Tregs, we found that Tregs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORα in skin-resident Tregs than in peripheral blood circulating Tregs in humans, suggesting that RORα and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.

IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice

Background: Serum IL‐22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2‐dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge–induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL‐22. Objective: We sought to determine the role of IL‐22 in antigen‐driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. Methods: Wild‐type (WT) and Il22−/− mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T‐cell receptor–specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. Results: Epicutaneous sensitization preferentially elicited an IL‐22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL‐22 production, and accumulation of CD3+CD4+IL‐22+ T cells that coexpressed IL‐17A and TNF‐&agr;. Epicutaneously sensitized Il22−/− mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL‐13, IL‐17A, and TNF‐&agr; was normal, but IFN‐&ggr; production was increased in lung cells from airway‐challenged and epicutaneously sensitized Il22−/− mice. Intranasal instillation of IFN‐&ggr;–neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22‐polarized WT, but not IL‐22–deficient, T‐cell receptor OVA‐specific T cells, which secrete both IL‐17A and TNF‐&agr;, had neutrophil‐dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL‐22 with TNF‐&agr;, but not IL‐17A, elicited neutrophil‐dominated airway inflammation and AHR in WT mice, suggesting that loss of IL‐22 synergy with TNF‐&agr; contributed to defective recruitment of neutrophils into the airways of Il22−/− mice. TNF‐&agr;, but not IL‐22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. Conclusion: Epicutaneous sensitization promotes generation of antigen‐specific IL‐22–producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL‐22 plays an important role in the atopic march. Graphical abstract Figure. No caption available.