Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis
Abstract Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)‐induced psoriasis‐like mice. Also, the SHP...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-12-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114455 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849342926137589760 |
|---|---|
| author | Yuyu Zhu Zhigui Wu Wei Yan Fenli Shao Bowen Ke Xian Jiang Jian Gao Wenjie Guo Yuping Lai Hongyue Ma Dijun Chen Qiang Xu Yang Sun |
| author_facet | Yuyu Zhu Zhigui Wu Wei Yan Fenli Shao Bowen Ke Xian Jiang Jian Gao Wenjie Guo Yuping Lai Hongyue Ma Dijun Chen Qiang Xu Yang Sun |
| author_sort | Yuyu Zhu |
| collection | DOAJ |
| description | Abstract Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)‐induced psoriasis‐like mice. Also, the SHP2 allosteric inhibitor SHP099 reduced pro‐inflammatory cytokine expression in PBMCs taken from psoriatic patients. Consistently, SHP099 significantly ameliorated IMQ‐triggered skin inflammation in mice. Single‐cell RNA sequencing of murine skin demonstrated that SHP2 inhibition impaired skin inflammation in myeloid cells, especially macrophages. Furthermore, IMQ‐induced psoriasis‐like skin inflammation was significantly alleviated in myeloid cells (monocytes, mature macrophages, and granulocytes)—but not dendritic cells conditional SHP2 knockout mice. Mechanistically, SHP2 promoted the trafficking of toll‐like receptor 7 (TLR7) from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, boosting the ubiquitination of TLR7 and NF‐κB‐mediated skin inflammation. Importantly, Tlr7 point‐mutant knock‐in mice showed an attenuated psoriasis‐like phenotype compared to wild‐type littermates following IMQ treatment. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients. |
| format | Article |
| id | doaj-art-7b0a4376e81f4df1be1193acb086c2c0 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7b0a4376e81f4df1be1193acb086c2c02025-08-20T03:43:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-12-0114312210.15252/emmm.202114455Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasisYuyu Zhu0Zhigui Wu1Wei Yan2Fenli Shao3Bowen Ke4Xian Jiang5Jian Gao6Wenjie Guo7Yuping Lai8Hongyue Ma9Dijun Chen10Qiang Xu11Yang Sun12State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityDepartment of Dermatology and Venereology, West China Hospital, Sichuan UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityLaboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital and State Key Laboratory of Biotherapy, Sichuan UniversityDepartment of Dermatology and Venereology, West China Hospital, Sichuan UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityShanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal UniversityCollege of Pharmacy, Nanjing University of Chinese MedicineState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing UniversityAbstract Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)‐induced psoriasis‐like mice. Also, the SHP2 allosteric inhibitor SHP099 reduced pro‐inflammatory cytokine expression in PBMCs taken from psoriatic patients. Consistently, SHP099 significantly ameliorated IMQ‐triggered skin inflammation in mice. Single‐cell RNA sequencing of murine skin demonstrated that SHP2 inhibition impaired skin inflammation in myeloid cells, especially macrophages. Furthermore, IMQ‐induced psoriasis‐like skin inflammation was significantly alleviated in myeloid cells (monocytes, mature macrophages, and granulocytes)—but not dendritic cells conditional SHP2 knockout mice. Mechanistically, SHP2 promoted the trafficking of toll‐like receptor 7 (TLR7) from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, boosting the ubiquitination of TLR7 and NF‐κB‐mediated skin inflammation. Importantly, Tlr7 point‐mutant knock‐in mice showed an attenuated psoriasis‐like phenotype compared to wild‐type littermates following IMQ treatment. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients.https://doi.org/10.15252/emmm.202114455psoriasisPTPN11scRNA‐seqtherapeutic targetTLR7 |
| spellingShingle | Yuyu Zhu Zhigui Wu Wei Yan Fenli Shao Bowen Ke Xian Jiang Jian Gao Wenjie Guo Yuping Lai Hongyue Ma Dijun Chen Qiang Xu Yang Sun Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis EMBO Molecular Medicine psoriasis PTPN11 scRNA‐seq therapeutic target TLR7 |
| title | Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis |
| title_full | Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis |
| title_fullStr | Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis |
| title_full_unstemmed | Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis |
| title_short | Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis |
| title_sort | allosteric inhibition of shp2 uncovers aberrant tlr7 trafficking in aggravating psoriasis |
| topic | psoriasis PTPN11 scRNA‐seq therapeutic target TLR7 |
| url | https://doi.org/10.15252/emmm.202114455 |
| work_keys_str_mv | AT yuyuzhu allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT zhiguiwu allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT weiyan allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT fenlishao allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT bowenke allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT xianjiang allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT jiangao allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT wenjieguo allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT yupinglai allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT hongyuema allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT dijunchen allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT qiangxu allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis AT yangsun allostericinhibitionofshp2uncoversaberranttlr7traffickinginaggravatingpsoriasis |