Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice
Abstract Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of skin disorders. We previously reported that Il36rn −/− mice exhibit an enhanced contact hypersensitivity (CHS) re...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-16449-z |
| _version_ | 1811344046515290112 |
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| author | Yurie Hasegawa Yohei Iwata Hidehiko Fukushima Yoshihito Tanaka Soichiro Watanabe Kenta Saito Hiroyuki Ito Mizuki Sugiura Masashi Akiyama Kazumitsu Sugiura |
| author_facet | Yurie Hasegawa Yohei Iwata Hidehiko Fukushima Yoshihito Tanaka Soichiro Watanabe Kenta Saito Hiroyuki Ito Mizuki Sugiura Masashi Akiyama Kazumitsu Sugiura |
| author_sort | Yurie Hasegawa |
| collection | DOAJ |
| description | Abstract Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of skin disorders. We previously reported that Il36rn −/− mice exhibit an enhanced contact hypersensitivity (CHS) response through increased neutrophil recruitment. In addition, Il36rn −/− mice show severe imiquimod-induced psoriatic skin lesions and enhanced neutrophil extracellular trap (NET) formation. We hypothesized that NETs may play an important role in the CHS response. To confirm this, we examined the CHS response and NET formation in Il36rn −/− mice. Il36rn −/− mice showed enhanced CHS responses, increased infiltration of inflammatory cells, including neutrophils, CD4+ T cells, and CD8+ T cells, NET formation, and enhanced mRNA expression of cytokines and chemokines, including IL-1β, C-X-C motif chemokine ligand (CXCL)1, CXCL2, and IL-36γ. Furthermore, NET formation blockade improved the CHS response, which consequently decreased inflammatory cell infiltration and NET formation. Consistently, we observed decreased expression of these cytokines and chemokines. These findings indicate that IL-36Ra deficiency aggravates the CHS response caused by excessive inflammatory cell recruitment, NET formation, and cytokine and chemokine production, and that NET formation blockade alleviates the CHS response. Thus, NET formation may play a prominent role in the CHS response. |
| first_indexed | 2024-04-13T19:40:48Z |
| format | Article |
| id | doaj.art-32411d106da94441868e51f1c7445b5e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T19:40:48Z |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-32411d106da94441868e51f1c7445b5e2022-12-22T02:32:53ZengNature PortfolioScientific Reports2045-23222022-08-011211910.1038/s41598-022-16449-zNeutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient miceYurie Hasegawa0Yohei Iwata1Hidehiko Fukushima2Yoshihito Tanaka3Soichiro Watanabe4Kenta Saito5Hiroyuki Ito6Mizuki Sugiura7Masashi Akiyama8Kazumitsu Sugiura9Department of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineDepartment of Dermatology, Nagoya University Graduate School of MedicineDepartment of Dermatology, Fujita Health University School of MedicineAbstract Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of skin disorders. We previously reported that Il36rn −/− mice exhibit an enhanced contact hypersensitivity (CHS) response through increased neutrophil recruitment. In addition, Il36rn −/− mice show severe imiquimod-induced psoriatic skin lesions and enhanced neutrophil extracellular trap (NET) formation. We hypothesized that NETs may play an important role in the CHS response. To confirm this, we examined the CHS response and NET formation in Il36rn −/− mice. Il36rn −/− mice showed enhanced CHS responses, increased infiltration of inflammatory cells, including neutrophils, CD4+ T cells, and CD8+ T cells, NET formation, and enhanced mRNA expression of cytokines and chemokines, including IL-1β, C-X-C motif chemokine ligand (CXCL)1, CXCL2, and IL-36γ. Furthermore, NET formation blockade improved the CHS response, which consequently decreased inflammatory cell infiltration and NET formation. Consistently, we observed decreased expression of these cytokines and chemokines. These findings indicate that IL-36Ra deficiency aggravates the CHS response caused by excessive inflammatory cell recruitment, NET formation, and cytokine and chemokine production, and that NET formation blockade alleviates the CHS response. Thus, NET formation may play a prominent role in the CHS response.https://doi.org/10.1038/s41598-022-16449-z |
| spellingShingle | Yurie Hasegawa Yohei Iwata Hidehiko Fukushima Yoshihito Tanaka Soichiro Watanabe Kenta Saito Hiroyuki Ito Mizuki Sugiura Masashi Akiyama Kazumitsu Sugiura Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice Scientific Reports |
| title | Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice |
| title_full | Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice |
| title_fullStr | Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice |
| title_full_unstemmed | Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice |
| title_short | Neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in IL-36 receptor antagonist-deficient mice |
| title_sort | neutrophil extracellular traps are involved in enhanced contact hypersensitivity response in il 36 receptor antagonist deficient mice |
| url | https://doi.org/10.1038/s41598-022-16449-z |
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