1. Academic Validation
  2. DAPT reverses the Th17/Treg imbalance in experimental autoimmune uveitis in vitro via inhibiting Notch signaling pathway

DAPT reverses the Th17/Treg imbalance in experimental autoimmune uveitis in vitro via inhibiting Notch signaling pathway

  • Int Immunopharmacol. 2020 Feb;79:106107. doi: 10.1016/j.intimp.2019.106107.
Xuewei Yin 1 Huixia Wei 1 Shanshan Wu 2 Zhe Wang 3 Bin Liu 1 Lijie Guo 4 Hongsheng Bi 5 Dadong Guo 6
Affiliations

Affiliations

  • 1 Shandong University of Traditional Chinese Medicine, Jinan 250002, China.
  • 2 School of Ophthalmology & Optometry, Shandong University of Traditional Chinese Medicine, Jinan 250002, China.
  • 3 Department of Ophthalmology, Zaozhuang Hospital of Traditional Chinese Medicine, Zaozhuang 277000, China.
  • 4 College of Life Sciences, Qingdao Agricultural University, Qingdao 266109, China.
  • 5 Shandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases, Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan 250002, China.
  • 6 Shandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases, Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan 250002, China. Electronic address: [email protected].
Abstract

Uveitis is the most common cause in inflammatory eye diseases that can lead to visual impairment even blindness worldwide. T helper (Th) 17 and regulatory T (Treg) cells are critical mediators for immune response. Notch signaling can regulate the cell differentiation, playing a role in the pathogenesis of the diseases. In this study, we measured the expression levels of Notch1, DLL4, IL-10, IL-17, RORγt and Foxp3 in T cells from lymph node, spleen and eye tissues in experimental autoimmune uveitis (EAU) rats in vitro, determined the ratios of CD4+/CD8+ and Th17/Treg. Moreover, we also investigated the effect of Notch signaling inhibitor N-(N-(3,5-Difluorophenacetyl-L-alanyl))-S-phenylglycine t-Butyl Ester (DAPT) on Notch1, DLL4 expression and on Th17, Treg cell differentiation. The results indicated that the pathogenesis of uveitis accompanied by the elevated expression of Notch1, DLL4, IL-10, IL-17, RORγt, and Foxp3 as well as the imbalanced CD4+/CD8+ and Th17/Treg ratios. By contrast, inhibition of Notch signaling by DAPT can efficiently decrease Th17 cell response, downregulate the expression of Notch1, DLL4, IL-17 and the transcription of RORγt, reduce Th17 levels and restore the CD4+/CD8+, Th17/Treg balance. Moreover, DAPT can also inhibit Th17 cell differentiation in healthy rats, though the inhibitory capacity of Th17, Treg differentiation is less than that in EAU rats. Overall, Notch signaling activation can lead to the disturbed Th17/Treg balance in uveitis, whereas inhibition of Notch signaling can ameliorate the inflammatory response and may be a potential immunoregulatory strategy in patients with uveitis.

Keywords

DAPT; Experimental autoimmune uveitis; Notch signaling; Th17/Treg.

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