Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk
Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through acti...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00746/full |
| _version_ | 1811272164359274496 |
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| author | Shuai Shao Hui Fang Erle Dang Ke Xue Jieyu Zhang Bing Li Hongjiang Qiao Tianyu Cao Yuchen Zhuang Shengxian Shen Tongmei Zhang Pei Qiao Caixia Li Johann E. Gudjonsson Gang Wang |
| author_facet | Shuai Shao Hui Fang Erle Dang Ke Xue Jieyu Zhang Bing Li Hongjiang Qiao Tianyu Cao Yuchen Zhuang Shengxian Shen Tongmei Zhang Pei Qiao Caixia Li Johann E. Gudjonsson Gang Wang |
| author_sort | Shuai Shao |
| collection | DOAJ |
| description | Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis. |
| first_indexed | 2024-04-12T22:35:21Z |
| format | Article |
| id | doaj.art-ce202e93be4a4b4db58ce639c8309f81 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T22:35:21Z |
| publishDate | 2019-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ce202e93be4a4b4db58ce639c8309f812022-12-22T03:13:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-04-011010.3389/fimmu.2019.00746424581Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R CrosstalkShuai Shao0Hui Fang1Erle Dang2Ke Xue3Jieyu Zhang4Bing Li5Hongjiang Qiao6Tianyu Cao7Yuchen Zhuang8Shengxian Shen9Tongmei Zhang10Pei Qiao11Caixia Li12Johann E. Gudjonsson13Gang Wang14Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Dermatology, University of Michigan, Ann Arbor, MI, United StatesDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaEpidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis.https://www.frontiersin.org/article/10.3389/fimmu.2019.00746/fullpsoriasisneutrophil extracellular trapsIL-36TLR4keratinocyte |
| spellingShingle | Shuai Shao Hui Fang Erle Dang Ke Xue Jieyu Zhang Bing Li Hongjiang Qiao Tianyu Cao Yuchen Zhuang Shengxian Shen Tongmei Zhang Pei Qiao Caixia Li Johann E. Gudjonsson Gang Wang Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk Frontiers in Immunology psoriasis neutrophil extracellular traps IL-36 TLR4 keratinocyte |
| title | Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk |
| title_full | Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk |
| title_fullStr | Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk |
| title_full_unstemmed | Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk |
| title_short | Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk |
| title_sort | neutrophil extracellular traps promote inflammatory responses in psoriasis via activating epidermal tlr4 il 36r crosstalk |
| topic | psoriasis neutrophil extracellular traps IL-36 TLR4 keratinocyte |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00746/full |
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