Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation

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.

Optimization of determinant factors associated with the efficiency of experimental autoimmune uveitis induction in C57BL/6 mice

“…Consistent with the clinical score, the HE score reached a peak level at day 18 (Figure 1B,1C). Our data were in line with previous reports in the literature on the EAU peak on days 16-21 (26,27). For retina flat mounts, FITC-conjugated isolectin-B4 (IB4) was adopted to identify both blood vessels and leukocytes, and CD4 + cells were identified by the specific immunofluorescent staining.…”

“…Currently, different types of peptide are available for EAU induction in rats or mice. Retinal soluble antigen (S-Ag) is commonly used in rats, while IRBP is mostly used in mice, with different mice strains manifesting different susceptibilities (26,31). Of note, the optimal dosage of IRBP 1-20 is central to the induction rate.…”

“…The emulsification technique has been adopted in various autoimmune disease models. In EAE, the emulsification methods were found to play a role in the induction of inflammation (26,28). The sonicated antigen/ adjuvant emulsion was shown to effectively induce EAE in the DBA/2 (H-2d) strain, whereas the conventional extruded emulsion only produced resistant EAE (29).…”

Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature

“…Nu. C. et al found that overexpressed kallistatin can aggravate experimental autoimmune uveitis (EAU) by accelerating the differentiation of Th17 cells [ 37 ]. Wang C et al found a significant decrease in the levels of the immune regulatory molecule progranulin in active VKH patients.…”

Neutrophil Extracellular Traps (NETs) in Ocular Diseases: An Update

“…KBP exhibits various functions, including angiogenesis, oxidative stress, inflammation, apoptosis, fibrosis, and tumor growth [ 86 ]. A recent study indicates that KBP is directly responsible for the differentiation of Th17 cells and the production of IL-17, which is a key regulator of aggravating autoinflammation in EAU [ 87 ].…”