ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils
Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about th...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.714274/full |
| _version_ | 1819128737755561984 |
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| author | Xiaonan Qiu Lin Zheng Lin Zheng Xiuting Liu Dan Hong Mintong He Zengqi Tang Cuicui Tian Guozhen Tan Sam Hwang Zhenrui Shi Liangchun Wang |
| author_facet | Xiaonan Qiu Lin Zheng Lin Zheng Xiuting Liu Dan Hong Mintong He Zengqi Tang Cuicui Tian Guozhen Tan Sam Hwang Zhenrui Shi Liangchun Wang |
| author_sort | Xiaonan Qiu |
| collection | DOAJ |
| description | Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis. |
| first_indexed | 2024-12-22T08:32:35Z |
| format | Article |
| id | doaj.art-f580f3b65fe640c885d51146fa3fbd21 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T08:32:35Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f580f3b65fe640c885d51146fa3fbd212022-12-21T18:32:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.714274714274ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With NeutrophilsXiaonan Qiu0Lin Zheng1Lin Zheng2Xiuting Liu3Dan Hong4Mintong He5Zengqi Tang6Cuicui Tian7Guozhen Tan8Sam Hwang9Zhenrui Shi10Liangchun Wang11Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaInstitute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaPsoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.https://www.frontiersin.org/articles/10.3389/fimmu.2021.714274/fullULK1 (unc-51 like autophagy activating kinase 1)psoriasiskeratinocyteneutrophilautophagy |
| spellingShingle | Xiaonan Qiu Lin Zheng Lin Zheng Xiuting Liu Dan Hong Mintong He Zengqi Tang Cuicui Tian Guozhen Tan Sam Hwang Zhenrui Shi Liangchun Wang ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils Frontiers in Immunology ULK1 (unc-51 like autophagy activating kinase 1) psoriasis keratinocyte neutrophil autophagy |
| title | ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils |
| title_full | ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils |
| title_fullStr | ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils |
| title_full_unstemmed | ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils |
| title_short | ULK1 Inhibition as a Targeted Therapeutic Strategy for Psoriasis by Regulating Keratinocytes and Their Crosstalk With Neutrophils |
| title_sort | ulk1 inhibition as a targeted therapeutic strategy for psoriasis by regulating keratinocytes and their crosstalk with neutrophils |
| topic | ULK1 (unc-51 like autophagy activating kinase 1) psoriasis keratinocyte neutrophil autophagy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.714274/full |
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