Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation.

Nu Chen,Lingzi Wu,Zhihui Zhang,Jian-Xing Ma,Shuang Chen,Kailei Guo,Hui Shao,Xuexue Cui,Xiaomin Zhang

doi:10.3389/fimmu.2021.756423

Abstract

Kallistatin or kallikrein-binding protein (KBP) has been reported to regulate angiogenesis, inflammation and tumor progression. Autoimmune uveitis is a common, sight-threatening inflammatory intraocular disease. However, the roles of kallistatin in autoimmunity and autoreactive T cells are poorly investigated. Compared to non-uveitis controls, we found that plasma levels of kallistatin were significantly upregulated in patients with Vogt-Koyanagi-Harada (VKH) disease, one of the non-infectious uveitis. Using an experimental autoimmune uveitis (EAU) model induced by human interphotoreceptor retinoid-binding protein peptide 651-670 (hIRBP651-670), we examined the effects of kallistatin on the pathogenesis of autoimmune diseases. Compared to wild type (WT) mice, kallistatin transgenic (KS) mice developed severe uveitis with dominant Th17 infiltrates in the eye. In addition, the proliferative antigen-specific T cells isolated from KS EAU mice produced increased levels of IL-17A, but not IFN-γ or IL-10 cytokines. Moreover, splenic CD4+ T cells from naïve KS mice expressed higher levels of Il17a mRNA compared to WT naïve mice. Under Th17 polarization conditions, KS mice exhibited enhanced differentiation of naïve CD4+ T cells into Th17 cells compared to WT controls. Together, our results indicate that kallistatin promotes Th17 differentiation and is a key regulator of aggravating autoinflammation in EAU. Targeting kallistatin might be a potential to treat autoimmune disease.

Highlights

Autoimmune uveitis or non-infectious uveitis (NIU) is a group of intraocular inflammatory disease, which can affect only the eyes, or it can be part of a systemic disease, and Vogt-KoyanagiHarada (VKH) is one of NIU [1]
The kallistatin-transgenic mice with same background of B6 were provided as a gift from Dr Jianxing Ma (University of Oklahoma Health Sciences Center), and the transgene expression was confirmed by real-time PCR (RT-PCR) of spleen and draining lymph nodes RNA using the genotyping primers
Much less attention has been paid to the role of kallistatin in the pathogenesis of autoimmune diseases

Summary

Introduction

Autoimmune uveitis or non-infectious uveitis (NIU) is a group of intraocular inflammatory disease, which can affect only the eyes, or it can be part of a systemic disease, and Vogt-KoyanagiHarada (VKH) is one of NIU [1]. More frequent occurrence in younger adults [4], autoimmune uveitis can cause heavy social and economic burdens. The pathogenesis of autoimmune uveitis remains unknown. Traditional therapeutic drugs, such as corticosteroids and immunosuppressants, when used for long periods of time, can yield a spectrum of local or systemic side effects. There is an urgent need to study pathological mechanisms of the autoimmune uveitis and explore effective drugs with strong pertinence and safety to treat autoimmune uveitis

Objectives

Methods

Results

Conclusion