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

Abstract

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 ...

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

“…These cytokines are believed rapidly signal barrier breach in order to generate innate immune responses and help prime adaptive immune cells. Strikingly, two recent studies have demonstrated that both TSLP and IL-33 can function as pruritogens (Liu et al, 2016; Wilson et al, 2013a). 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).…”

Spinal IL‐33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2‐STAT3 cascade

“…In a recent study, the role of peripheral IL‐33/ST2 signaling in a poison ivy‐induced ACD mouse model was illustrated. Inflamed skin‐derived IL‐33 was found to act on ST2, expressed in dorsal root ganglion neurons, and mediate itch (Liu, Tai, et al, ). Also, it is demonstrated that anti‐mouse IL‐33 antibody via subcutaneous injection remarkably reduced the scratching behaviors in the 2,4‐dinitrochlorobenzene‐induced AD mice (Peng et al, ).…”

Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family

“…Although they are less well characterized, non‐immune cells may also constitute important cellular targets of IL‐33 in vivo. These include endothelial cells, epithelial cells, fibroblasts, astrocytes, and neurons …”