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  3. Loss of tricellular tight junction tricellulin leads to hyposalivation in Sjögren's syndrome

Loss of tricellular tight junction tricellulin leads to hyposalivation in Sjögren's syndrome

  • Int J Oral Sci. 2025 Mar 19;17(1):22. doi: 10.1038/s41368-025-00349-9.
Xiangdi Mao 1,  Haibing Li 1,  Sainan Min 2,  Jiazeng Su 2,  Pan Wei 3,  Yan Zhang 1,  Qihua He 4,  Liling Wu 1,  Guangyan Yu 2,  Xin Cong 5 6
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing, China.
  • 2 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China.
  • 3 Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
  • 5 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing, China. congxin@bjmu.edu.cn.
  • 6 Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China. congxin@bjmu.edu.cn.
PMID: 40108118 DOI: 10.1038/s41368-025-00349-9
Abstract

Tricellulin, a key tricellular tight junction (TJ) protein, is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands. This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren's syndrome (SS). Employing a multifaceted approach involving patient biopsies, non-obese diabetic (NOD) mice as a SS model, salivary gland acinar cell-specific tricellulin conditional knockout (TricCKO) mice, and IFN-γ-stimulated salivary gland epithelial cells, we investigated the role of tricellulin in SS-related hyposalivation. Our data revealed diminished levels of tricellulin in salivary glands of SS patients. Similarly, NOD mice displayed a reduction in tricellulin expression from the onset of the disease, concomitant with hyposecretion and an increase in salivary albumin content. Consistent with these findings, TricCKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control Animals. Mechanistically, the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin. Treatment with AT1001, a TJ sealer, ameliorated epithelial barrier dysfunction, restored tricellulin expression, and consequently alleviated hyposalivation in NOD mice. Importantly, treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage. Collectively, we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS. Our findings highlight tricellulin as a potential therapeutic target for hyposecretion, particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.

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