TSLP elicits IL-33–independent innate lymphoid cell responses to promote skin inflammation

By Brian S. Kim, M. Siracusa, S. Saenz, M. Noti, L. Monticelli, Gregory F. Sonnenberg, M. Hepworth, A. V. Van Voorhees, M. Comeau, D. Artis. Science Translational Medicine, 2013

720 citations recorded by the source corpus.

Group 2 innate lymphoid cells are essential to the pathogenesis of atopic dermatitis–like disease in a TSLP-dependent, IL-33–independent manner. Immune Cell Activity at the Skin Barrier The skin acts like soft armor, protecting the body from disease and environmental insults. In atopic dermatitis (AD), this barrier is disrupted, leading to inflammation. The role of various immune cells in this chronic disease has not been clear. Now, Kim and colleagues identify a subset of innate lymphoid cells (ILCs) in both human and mouse skin that contribute to disease pathogenesis. ILCs have been reported in inflamed nasal polyps in people, as well as in inflamed lungs in mice. Hypothesizing that they also play a role in skin inflammation, Kim et al. analyzed cells isolated from the skin tissue of healthy control subjects and from the lesions of AD patients. There were more Lin− CD25+ IL-33R+ RORγt− group 2 ILCs (ILC2s) in the lesions of AD patients. In healthy mouse skin, the authors identified a similar ILC2 population. AD in humans is linked to cytokines interleukin-33 (IL-33), IL-25, and thymic stromal lymphopoietin (TSLP) in the skin. To this end, the authors investigated in mice whether the ILC2s played a role in inflammation at the skin barrier and if they were dependent on these cytokines. In a mouse model of AD, Kim et al. noted that ILC2s were increased and that AD pathogenesis was initiated independently of adaptive immunity and RORγt+ cells (a marker of group 3 ILCs). The mechanism was also independent of IL-25 and IL-33—which are normally implicated in group 2 ILC responses—yet dependent on TSLP. Depletion of the ILCs attenuated AD-like dermatitis in mice. Group 2 ILCs have not yet been described in skin barrier function in humans. In these studies, Kim and colleagues show that ILC2s are always present in healthy skin, but accumulate in AD lesions and function by a mechanism that contrasts what has been reported in lungs and intestine. Future functional studies will be needed for human ILC2s in skin inflammation, but these preliminary data in mice and humans suggest that targeting group 2 ILCs will be a viable target for treating AD and other allergic diseases. 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 interleukin-5 (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. We identify 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, group 2 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.

Subfields: Dermatology, Immunology

View Paper: https://www.semanticscholar.org/paper/ce0f44136b47aab617076193273bf3c94e62c8ae

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

Citations in the corpus

Innate Lymphoid Cells: a new paradigm in immunology (2015, background): “ILC2s and IL-13 are also associated with hepatic fibrosis induced in mice by thioacetamide, carbontetrachloride, and Schistosoma mansoni (109), and with pulmonary fibrosis (108), chronic rhinosinusitis (110), and atopic dermatitis (111, 112), as well as allergen- (112, 113) and rhinovirusinduced ast”
Innate lymphoid cells and asthma. (2014, positive): “These studies include reports of ILC2s in fetal gut tissue, which were identified as Lin2, IL-7 receptor a (CD127)1 cells expressing chemoattractant receptor–homologous molecule expressed on TH2 cells (CRTH2) and CD161,58 in the pleural effusion of patients with primary spontaneous pneumothorax asso”
Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch (2017, neutral): “Additionally, we and others have shown that epithelial cell-derived cytokines are highly expressed in the setting of AD-like disease (Kim et al., 2013; Li et al., 2006; Salimi et al., 2013).”
A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis (2013, background): “One difference between Kim et al. (2013) and this study was their use of the C57BL/6 strain mouse.”