2. Academic Validation
  3. Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis

Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis

  • EMBO Mol Med. 2022 Mar 7;14(3):e14455. doi: 10.15252/emmm.202114455.
Yuyu Zhu  # 1 2,  Zhigui Wu  # 1,  Wei Yan  # 3,  Fenli Shao  # 1,  Bowen Ke 4,  Xian Jiang 3,  Jian Gao 1,  Wenjie Guo 1,  Yuping Lai 5,  Hongyue Ma 2,  Dijun Chen 1,  Qiang Xu 1,  Yang Sun 1 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing, China.
  • 2 College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China.
  • 4 Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
  • 5 Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
  • 6 Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
  • # Contributed equally.
PMID: 34936223 DOI: 10.15252/emmm.202114455
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.

Keywords

PTPN11; TLR7; psoriasis; scRNA-seq; therapeutic target.

Figures
Products