TSLP Elicits IL-33–Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation

Abstract

Innate lymphoid cells (ILCs) are a recently identified family of heterogeneous immune cells that can be divided into three groups based on their differential developmental requirements and expression of effector cytokines. Among these, group 2 ILCs produce the type 2 cytokines IL-5 and IL-13 and promote type 2 inflammation in the lung and intestine. However, whether group 2 ILCs reside in the skin and contribute to skin inflammation has not been characterized. Here, we identify for the first time a population of skin-resident group 2 ILCs present in healthy human skin that are enriched in lesional human skin from atopic dermatitis (AD) patients. Group 2 ILCs were also found in normal murine skin and were critical for the development of inflammation in a murine model of AD-like disease. Remarkably, in contrast to group 2 ILC responses in the intestine and lung, which are critically regulated by IL-33 and IL-25, ILC responses in the skin and skin-draining lymph nodes were independent of these canonical cytokines but were critically dependent on thymic stromal lymphopoietin (TSLP). Collectively, these results demonstrate an essential role for IL-33– and IL-25–independent group 2 ILCs in promoting skin inflammation.

New insights in the pathogenesis of atopic dermatitis

“…They are divided into three groups: group 1 ILCs are IFN-γ-producing cells that include natural killer cells; group 2 ILCs produce IL-13, IL-5, and/or IL-4; and group 3 ILCs produce IL-17 and IL-22 (21). Group 2 ILCs were shown to be significantly increased in human AD lesions, as compared to healthy skin (20).…”

“…TSLP activates dendritic cells (DC) to produce chemokines such as thymus-and activation-regulated chemokine/ chemokine (C-C motif) ligand (CCL)17 and macrophagederived chemokine/CCL22, which leads to infiltration of Th2 cells in AD lesions (19). In a recent AD mouse model, TSLP was shown to activate cutaneous group 2 innate lymphoid cells (ILCs; Figure 1) (20). ILCs are characterized by their lymphoid morphology, but lack recombination-activating genedependent rearrangement antigen receptors and myeloid/ dendritic cell markers (20).…”

“…In a recent AD mouse model, TSLP was shown to activate cutaneous group 2 innate lymphoid cells (ILCs; Figure 1) (20). ILCs are characterized by their lymphoid morphology, but lack recombination-activating genedependent rearrangement antigen receptors and myeloid/ dendritic cell markers (20). They are divided into three groups: group 1 ILCs are IFN-γ-producing cells that include natural killer cells; group 2 ILCs produce IL-13, IL-5, and/or IL-4; and group 3 ILCs produce IL-17 and IL-22 (21).…”

Les cellules lymphoïdes innées

“…Cet enrichissement est aussi observé chez les patients atteints de rhinosinusite chronique [1] et dans les lésions inflammatoires de dermatite atopique, chez l'homme comme chez la souris. Leur déplétion atténue les symptômes cutanés chez la souris [49]. Dans les poumons, les ILC2 sont à l'origine de l'inflammation allergique provoquée, dans le modèle murin, par l'administration intranasale de l'allergène papaïne, et de l'hyperréactivité pulmonaire que l'on observe après une infection par le virus de la grippe [23].…”

Regulatory roles of dermal type 2 innate lymphoid cells

“…On the other hand, another independent research group has demonstrated that skin-resident ILC2s are indispensible for atopic dermatitis (AD)-like disease induced by the vitamin D3 analog MC903. 6 This chemical is a potent inducer of TSLP (but not IL-25 and IL-33) production by keratinocytes. Which cytokine is produced among IL-25, IL-33 and TSLP at mucosal barriers seems to be determined by types of allergens, parasites and other injury inducers, and responding parenchymal and stromal cells.…”