Keratinocyte TLR2 and TLR7 contribute to chronic itch through pruritic cytokines and chemokines in mice |
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| Authors: | Zhi-Hong Wang Yu Feng Qingfang Hu Xue-Long Wang Li Zhang Teng-Teng Liu Jiang-Tao Zhang Xiaohua Yang Qing-Yue Fu Dan-Ni Fu Ji Hu Tong Liu |
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| Institution: | 1. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China;2. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China;3. Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital Beijing, Beijing, China;4. Department of Anesthesiology, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Kunshan, China;5. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China;6. Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, China;7. The Affiliated Haian Hospital of Nantong University, Haian, China |
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| Abstract: | Although neuronal Toll-like receptors (TLRs) (e.g., TLR2, TLR3, and TLR7) have been implicated in itch sensation, the roles of keratinocyte TLRs in chronic itch are elusive. Herein, we evaluated the roles of keratinocyte TLR2 and TLR7 in chronic itch under dry skin and psoriasis conditions, which was induced by either acetone-ether-water treatment or 5% imiquimod cream in mice, respectively. We found that TLR2 and TLR7 signaling were significantly upregulated in dry skin and psoriatic skin in mice. Chronic itch and epidermal hyperplasia induced by dry skin or psoriasis were comparably reduced in TLR2 and TLR7 knockout mice. In the dry skin model, the enhanced messenger RNA (mRNA) expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, TNF-α, and IFN-γ were inhibited in TLR2−/− mice, while CXCL2, IL-31, and IL-6 were inhibited in TLR7−/− mice. In psoriasis model, the enhanced mRNA expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, and TNF-α were inhibited in TLR2−/− mice, while CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, and TNF-α were inhibited in TLR7−/− mice. Incubation with Staphylococcus aureus (S. aureus) peptidoglycan (PGN-SA) (a TLR2 agonist), imiquimod (a TLR7 agonist), and miR142-3p (a putative TLR7 agonist) were sufficient to upregulate the expression of pruritic cytokines or chemokines in cultured keratinocyte HaCaT cells. Finally, pharmacological blockade of C-X-C Motif Chemokine Receptor 1/2 and high mobility group box protein 1 dose-dependently attenuated acute and chronic itch in mice. Together, these results indicate that keratinocyte TLR2 and TLR7 signaling pathways are distinctly involved in the pathogenesis of chronic itch. |
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| Keywords: | chemokine cytokine itch keratinocyte TLR2 TLR7 |
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