IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjögren's syndrome

Fan Xiao; Wenhan Du; Xiaoxia Zhu; Yuan Tang; Lixiong Liu; Enyu Huang; Chong Deng; Cainan Luo; Man Han; Ping Chen; Liping Ding; Xiaoping Hong; Lijun Wu; Quan Jiang; Hejian Zou; Dongzhou Liu; Liwei Lu

doi:10.1002/cti2.1277

IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjögren's syndrome

Clin Transl Immunology. 2021 Apr 29;10(4):e1277. doi: 10.1002/cti2.1277. eCollection 2021.

Authors

Fan Xiao^{1

2}, Wenhan Du^{1

2}, Xiaoxia Zhu³, Yuan Tang^{1

2}, Lixiong Liu⁴, Enyu Huang^{1

2}, Chong Deng^{1

2}, Cainan Luo⁵, Man Han⁶, Ping Chen⁴, Liping Ding⁴, Xiaoping Hong⁴, Lijun Wu⁵, Quan Jiang⁶, Hejian Zou³, Dongzhou Liu⁴, Liwei Lu^{1

2}

Affiliations

¹ Department of Pathology Shenzhen Institute of Research and Innovation The University of Hong Kong Hong Kong.
² Chongqing International Institute for Immunology Chongqing China.
³ Department of Rheumatology Huashan Hospital and Fudan University Shanghai China.
⁴ Department of Rheumatology and Immunology Second Clinical Medical College of Jinan University Shenzhen People's Hospital Shenzhen China.
⁵ Department of Rheumatology and Immunology People's Hospital of Xinjiang Uygur Autonomous Region Urumqi China.
⁶ Division of Rheumatology Guang'anmen Hospital China Academy of Chinese Medical Sciences Beijing China.

Abstract

Objectives: This study aims to determine a role of interleukin-17A (IL-17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL-17 in SG for treating autoimmune sialadenitis in primary Sjögren's syndrome (pSS).

Methods: Salivary IL-17 levels and IL-17-secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL-17-producing cells in SG from mice with experimental Sjögren's syndrome (ESS) were analysed. To determine a role of IL-17 in salivary secretion, IL-17-deficient mice and constructed chimeric mice with IL-17 receptor C (IL-17RC) deficiency in non-hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL-17 for measuring cholinergic activation-induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL-17 neutralisation antibodies.

Results: Increased salivary IL-17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL-17-deficient mice and chimeric mice with non-hematopoietic cell-restricted IL-17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell-restricted IL-17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL-17 inhibited acetylcholine-induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL-17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice.

Conclusion: These findings identify a novel function of IL-17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.

Keywords: IL‐17; autoimmune sialadenitis; calcium movement; primary Sjögren’s syndrome; salivary dysfunction.