Targeting TBK1 attenuates ocular inflammation in uveitis by antagonizing NF-κB signaling

Si Chen; Jinfeng Kong; Shiying Wu; Chenqi Luo; Junhui Shen; Zhaocai Zhang; Jian Zou; Lei Feng

doi:10.1016/j.clim.2022.109210

Targeting TBK1 attenuates ocular inflammation in uveitis by antagonizing NF-κB signaling

Clin Immunol. 2023 Jan:246:109210. doi: 10.1016/j.clim.2022.109210. Epub 2022 Dec 14.

Authors

Si Chen¹, Jinfeng Kong², Shiying Wu³, Chenqi Luo², Junhui Shen², Zhaocai Zhang⁴, Jian Zou⁵, Lei Feng⁶

Affiliations

¹ Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Department of ophthalmology, Jinshan Branch of Shanghai Sixth People's Hospital, Shanghai 201599, China.
² Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
³ Key Laboratory for Food Microbial Technology of Zhejiang Province, Department of Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
⁴ Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310009, China. Electronic address: 2313003@zju.edu.cn.
⁵ Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; The Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. Electronic address: jianzou@zju.edu.cn.
⁶ Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China. Electronic address: leifeng@zju.edu.cn.

PMID: 36528252
DOI: 10.1016/j.clim.2022.109210

Abstract

Uveitis with complex pathogenesis is a kind of eye emergency involving refractory and blinding inflammation. Dysregulation of TANK binding kinase 1 (TBK1), which plays an important role in innate immunity, often leads to inflammatory diseases in various organs. However, the role of TBK1 in uveitis remains elusive. In this study, we identified that the mRNA expression level of TBK1 and its phosphorylation level were significantly increased in peripheral blood mononuclear cells (PBMCs) of patients with uveitis. Consistent with this, the expression of Tbk1 was elevated in the ocular tissues of uveitis rats and primary peritoneal macrophages while its phosphorylation levels, which present activation forms, were upregulated as well, accompanied by an increase in the level of nuclear factor-κB (NF-κB) and proinflammatory cytokines. In addition, inhibition of TBK1 may effectively reduce the inflammatory response of uveitis rats by blocking NF-κB entry into the nucleus and impeding the initiation of NLRP3 inflammasome- and caspase-1-mediated pyroptosis pathways.

Keywords: GSK8612; Inflammatory cytokine; NF-κB; Pyroptosis; TBK1; Uveitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Inflammasomes / metabolism
Inflammation / metabolism
Leukocytes, Mononuclear / metabolism
NF-kappa B* / metabolism
Rats
Signal Transduction
Uveitis* / genetics

Substances

Inflammasomes
NF-kappa B
Tbk1 protein, rat