2. Academic Validation
  3. Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation

Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation

  • Pharmacol Res. 2021 Jul:169:105679. doi: 10.1016/j.phrs.2021.105679.
Weilian Bao 1,  Xiaohong Liu 2,  Yan You 3,  Hui Hou 2,  Xu Wang 1,  Sulin Zhang 2,  Haidong Li 1,  Guize Feng 1,  Xinyu Cao 1,  Hualiang Jiang 4,  Mingyue Zheng 5,  Xiaoyan Shen 6
Affiliations

Affiliations

  • 1 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; National Institute of Allergy and Infectious, National Institute of Health, Rockville, MD, USA.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: [email protected].
  • 5 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 34010669 DOI: 10.1016/j.phrs.2021.105679
Abstract

Sorting nexin 10 (SNX10) has been reported as a critical regulator in macrophage function, and germline SNX10 knockout effectively alleviated mouse colitis. Here, we investigated the precise role of SNX10 in inflammatory responses in macrophages in mouse colitis, and explored the druggability of SNX10 as a therapeutic target for inflammatory bowel disease (IBD). Our results revealed that myeloid-specific SNX10 deletion alleviated inflammation and pathological damage induced by dextran sulfate sodium (DSS). In vitro experiments showed that SNX10 deletion contributed to inflammation elimination by inhibiting PIKfyve-mediated TANK-binding kinase 1 (TBK1) /c-Rel signaling activation. Further study provided rational mechanism that SNX10 was required for the recruitment of PIKfyve to the TRIF-positive endosomes, through which PIKfyve activated TBK1/c-Rel for LPS-induced inflammation response. Based on the structure of SNX10, we discovered a new small-molecule inhibitor DC-SX029, which targeted SNX10 to block the SNX10-PIKfyve interaction, thereby decreased the TBK1/c-Rel signaling activation. Additionally, therapeutic efficiency of DC-SX029 was evaluated in both DSS-induced and IL10-deficient mouse colitis models. Our data demonstrate a new mechanism by which SNX10-PIKfyve interaction regulates LPS-induced inflammation response in macrophages via the TBK1/c-Rel signaling pathway. In vivo and in vitro pharmacological studies of SNX10 protein-protein interaction (PPI) inhibitor DC-SX029 demonstrate the feasibility of targeting SNX10 in IBD treatment.

Keywords

IBD; Macrophage; PIKfyve; PPI inhibitor; SNX10; TBK1.

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