Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice

Imai, Yasutomo; Yasuda, Koubun; Sakaguchi, Yoshiko; Haneda, Takashi; Mizutani, Hitoshi; Yoshimoto, Tomohiro; Nakanishi, Kenji; Yamanishi, Kiyofumi

doi:10.1073/pnas.1307321110

Cited by 382 publications

(353 citation statements)

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“…IL-33 expression is also enhanced in human ACD skin (21). More importantly, skin-specific expression of IL-33 can elicit atopic dermatitis-like inflammation and scratching behavior in mice (22). In the present study, we therefore investigated the possible involvement of this cytokine in itch caused by poison ivy ACD.…”

Section: Resultsmentioning

confidence: 91%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

223

195

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Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO 2 . Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca 2+ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.A llergic contact dermatitis (ACD) is a common allergic skin condition caused by environmental or occupational allergens (1). In the United States, the most common cause of ACD is contact with poison ivy, which affects >10 million Americans per year (2, 3). Poison ivy ACD is also a serious occupational hazard, particularly among firefighters, forestry workers, and farmers, accounting for 10% of total U.S. Forest Services losttime injuries, and it often torments outdoor enthusiasts as well (3, 4). The major allergen in poison ivy is urushiol, contained in the oleoresinous sap of the plant and of related plants (e.g., poison oak and poison sumac) (5). An estimated 50-75% of Americans are sensitized to urushiol (6). Elevated atmospheric carbon dioxide and warming temperatures have increased the biomass of poison ivy and related plants, widened their geographic distribution, and increased plant urushiol content (7). These factors will likely increase allergenicity and result in even larger case numbers of poison ivy ACD in the future (8).The clinical manifestations of poison ivy-induced ACD are intense and persistent itch (pruritus), burning sensation, skin rashes, and swelling, followed by the appearance of vesicles in severe cases (2, 3, 9). Skin inflammation and pruritus ...

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Section: Resultsmentioning

confidence: 91%

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Liu

Tai

Achanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

223

195

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“…In the skin, ILC2s have been shown to be predominantly regulated by TSLP during AD-like disease (Kim et al 2013a). However, recent studies showed that IL-25 and IL-33 may also have relevant roles in AD-like inflammation (Imai et al 2013;Salimi et al 2013). Collectively, whether IL-25, IL-33, or TSLP is the dominant cytokine for the activation and/or elicitation of ILC2s at different barrier surfaces remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Further, skin-associated ILC2s could directly induce AD-like pathology and T H 2 cell responses in vivo (Kim et al 2013a). A more recent study confirmed the presence of ILC2s in murine skin and used transgenic mice overexpressing IL-33 under a keratin 14 promoter to show that IL-33 expression can also drive AD-like inflammation and the expansion of ILC2s in the skin (Imai et al 2013). Recently, Salimi et al (2013) confirmed that skin ILC2s are dependent on TSLP in C57BL/6 mice and found that there is partial dependence on both IL-25 and IL-33 in the development of skin ILC2 responses in BALB/ c (but not C57BL/6) mice during AD-like inflammation.…”

Section: Ilc2s In the Skin Atopic Dermatitismentioning

confidence: 97%

Group 2 Innate Lymphoid Cells in Health and Disease

Kim

Artis

2015

Cold Spring Harb Perspect Biol

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Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity, airway epithelial repair, and metabolic homeostasis. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORa, GATA3, and TCF-1, and produce the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, and/or IL-13. The epithelial cell -derived cytokines IL-25, IL-33, and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of the various factors that regulate ILC2 function in the context of immunity, inflammation, and tissue repair across multiple organ systems.

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“…These cells control eosinophil homeostasis in blood and adipose tissue (18,19) and produce extremely high amounts of the type-2 cytokines IL-5 and IL-13 in response to IL-33 (14)(15)(16). ILC2s also play important roles in allergic airway inflammation (20)(21)(22)(23)(24), atopic skin disease (25)(26)(27)(28), helminth infection in the intestine (11,12,(14)(15)(16), and influenza virus infection in the lungs (29,30).…”

mentioning

confidence: 99%

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

Lefrançais

Duval

Mirey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

321

310

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Interleukin-33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 activates many immune cell types expressing the interleukin 1 receptor-like 1 (IL1RL1) receptor ST2, including group-2 innate lymphoid cells (ILC2s, natural helper cells, nuocytes), the major producers of IL-5 and IL-13 during type-2 innate immune responses and allergic airway inflammation. IL-33 is likely to play a critical role in asthma because the IL33 and ST2/IL1RL1 genes have been reproducibly identified as major susceptibility loci in large-scale genome-wide association studies. A better understanding of the mechanisms regulating IL-33 activity is thus urgently needed. Here, we investigated the role of mast cells, critical effector cells in allergic disorders, known to interact with ILC2s in vivo. We found that serine proteases secreted by activated mast cells (chymase and tryptase) generate mature forms of IL-33 with potent activity on ILC2s. The major forms produced by mast cell proteases, IL-33 95-270 , IL-33 107-270 , and IL-33 109-270 , were 30-fold more potent than full-length human IL-33 1-270 for activation of ILC2s ex vivo. They induced a strong expansion of ILC2s and eosinophils in vivo, associated with elevated concentrations of IL-5 and IL-13. Murine IL-33 is also cleaved by mast cell tryptase, and a tryptase inhibitor reduced IL-33-dependent allergic airway inflammation in vivo. Our study identifies the central cleavage/activation domain of IL-33 (amino acids 66-111) as an important functional domain of the protein and suggests that interference with IL-33 cleavage and activation by mast cell and other inflammatory proteases could be useful to reduce IL-33-mediated responses in allergic asthma and other inflammatory diseases.cytokine | IL-33 | allergic inflammation | mast cell protease | innate lymphoid cells

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Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice

Cited by 382 publications

References 33 publications

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy

Group 2 Innate Lymphoid Cells in Health and Disease

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

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