<scp>IL</scp>‐33 drives airway hyper‐responsiveness through <scp>IL</scp>‐13‐mediated mast cell: airway smooth muscle crosstalk

Kaur, Davinder; Gomez, Edith; Doe, Camille; Berair, Rachid; Woodman, Lucy; Saunders, Ruth; Hollins, Fay; Rose, Felicity R. A. J.; Amrani, Yassine; May, Richard; Kearley, Jennifer; Humbles, AA; Cohen, E. Suzanne; Brightling, Christopher E.

doi:10.1111/all.12593

Cited by 147 publications

(148 citation statements)

References 47 publications

(48 reference statements)

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“…It is known that ST2 is expressed in Th2 cells, in a variety of innate immune cells as well as in skin cells (23). IL-33 can interact with keratinocytes, mast cells, and other immune cells through ST2 to produce proinflammatory mediators and cytokines, including TSLP, histamine, serotonin, and IL-13, that have known roles in the initiation of allergic diseases and itch (35,(38)(39)(40). Our in vivo experiments using ST2-neutralizing antibodies may have interfered with the actions of these cells types in addition to the sensory neurons.…”

Section: Discussionmentioning

confidence: 99%

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.

212

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: Discussionmentioning

confidence: 99%

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.

212

195

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“…Not only is the relationship between ASM and matrix important in determining function, but equally it has been proposed that the presence of inflammatory cells, specifically mast cells, within ASM bundles is pathognomic of asthma [72]. Cross-talk between mast cells and ASM has been shown to directly induce AHR via IL-33 [73]. Bitter taste receptors have been highlighted as a potential novel target for asthma as they were found to be expressed on murine ASM and their agonists caused smooth muscle relaxation [74].…”

Section: Airway Smooth Musclementioning

confidence: 99%

Novel concepts in airway inflammation and remodelling in asthma

2015

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The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. @ERSpublications We discuss mechanisms of airway inflammation and remodelling in asthma to uncover effective therapeutic strategies http://ow.ly/SsXiO

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“…IL-33 induced Th-17-mediated airway inflammation via MCs (Hsu et al, 2010). In fact, there is evidence that IL-33 modulates cross-talk between MCs and smooth muscle cells in human airways (Kaur et al, 2015). Genetic polymorphism of ST2 and ST2L provides susceptibility for asthma development (Moffatt et al, 2010).…”

Section: Functional and Pathologic Features Of Il-33 In Allergic Disementioning

confidence: 99%

Targeting IL-33 in Autoimmunity and Inflammation

Theoharides

Petra

Taracanova

et al. 2015

J Pharmacol Exp Ther

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IL‐33 drives airway hyper‐responsiveness through IL‐13‐mediated mast cell: airway smooth muscle crosstalk

Cited by 147 publications

References 47 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

Novel concepts in airway inflammation and remodelling in asthma

Targeting IL-33 in Autoimmunity and Inflammation

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