IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.
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 CO2Severe 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 Ca2+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.
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China; sven.jordt@duke.edu boyi.liu@foxmail.com.|Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710.
Boyi
B
Liu
Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710.
Yan
Y
Tai
Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710.
Satyanarayana
S
Achanta
Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710.
Melanie M
MM
Kaelberer
Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710.
Ana I
AI
Caceres
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
Xiaomei
X
Shao
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
Jianqiao
J
Fang
Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710 sven.jordt@duke.edu boyi.liu@foxmail.com.
Sven-Eric
SE
Jordt
D000818:Animals; D002396:Catechols / Q000009:adverse effects; D011040:Dermatitis, Toxicodendron / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics* / Q000378:metabolism; D000067596:Interleukin-33 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D015854:Up-Regulation
D002396:Catechols; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; C003747:urushiol
IL-33; allergic contact dermatitis; cytokine; itch; pain