Blockade of IL-27 signaling ameliorates herpes stromal keratitis with upregulated CD4⁺Foxp3⁺regulatory T cells influx in mice

Abstract

Purpose:The purpose of this study was to investigate the production of IL-27 p28 and EBI3 in the ocular inflammatory sites, and the role of IL-27 signaling in a model of HSV-1 induced herpetic stromal keratitis (HSK).Methods:The BALB/c mice were injected intraperitoneally (24 h before infection) with anti-IL-27 antibody or IgG antibody as control, infected with HSV-1 via corneal scarification, and then injected intraperitoneally with anti-IL-27 antibody or IgG antibody at 1, 3, and 5 days postinfection. Slit lamp and histopathology were used to assess disease outcome. The levels of IL-27 p28 and EBI3 in corneas were determined by western blotting and immunofluorescence. Furthermore, viral titers were determined, and immune cell infiltrates were collected and analyzed by flow cytometry.Results:We found that the levels of IL-27 p28 and EBI3 in corneas were elevated significantly at the peak of HSK, and both of them were expressed simultaneously in the epithelium, stroma, and endothelium of corneas. In the group of anti-IL-27 treatment, the severity of the corneal lesion and CD4+ T cells infiltration were significantly decreased, and the percentage of CD4+ Foxp3+ Tregs was upregulated markedly in the spleen, DLNs and cornea of HSK mice compared to IgG treatment.Conclusion:These results provided evidence that IL-27 as a pathogenic pro-inflammatory cytokine controlled CD4+ Foxp3+ Tregs production in HSK, which ultimately resulted in promoting the progression of HSK and poor prognosis.

Pathogenesis of Herpes Stromal Keratitis: Immune Inflammatory Response Mediated by Inflammatory Regulators

“…Moreover, CD4 + CD25 + Tregs can also protect the cornea from more severe lesions, and depletion of CD4 + CD25 + Tregs can accelerate HSK progression (34). A recent study reported that treating the virus-induced inflammatory response with anti-IL-27 antibody can increase the numbers of CD4 + Foxp3 + Tregs, ameliorating tissue damage in the cornea (35). Collectively, Tregs play a protective role in maintaining homeostasis, enhancing immunological tolerance, and preventing autoimmune diseases.…”

Activation of the STAT5 Signaling Pathway by Yiqi Jiedu Formula Induces Regulatory T Cell-Mediated Alleviation of Corneal Immunopathological Damage in Mice With Recurrent Herpes Simplex Keratitis

“…HSK, a chronic immunopathological lesion, has been shown to severely impair visual quality (Rajasagi et al, 2017). In particular, over the course of blinding inflammation of the ocular surface, an inadequate immune response increases disease susceptibility, whereas an overreaction induces corneal clouding through inflammatory cell damage; this indicates that balanced immunopathological responses are crucial for preventing corneal clouding, scar formation, and permanent vision loss (Xia et al, 2019). Tregs and the cytokines IL-10 and TGF-β play a protective role by maintaining homeostasis, enhancing immune tolerance, and preventing the onset of autoimmune diseases.…”

“…Notably, bilateral disease, recurrent infections, and CS are observed more frequently in immunocompromised patients (Liesegang, 2001). Moreover, a recent study showed that treatment of virus-induced inflammatory responses with anti-IL-27 antibodies increased the number of CD4 + CD25 + Foxp3 + Treg cells and improved corneal tissue damage during relapses (Xia et al, 2019). Overall, previous research has demonstrated that Tregs play a protective role by maintaining homeostasis in vivo, enhancing immune tolerance, improving corneal damage, and preventing the onset of autoimmune diseases.…”

Commentary: Targeting herpetic keratitis by immunomodulation of IL-27 signaling

“…In this issue of the Indian Journal of Ophthalmology , Xia et al investigate the role of IL-27 signaling in HSV-1 infection using a mouse model of HSK. [4] IL-27 is a heterodimeric cytokine composed of the subunits p28 and EBI3, which bind to the heterodimeric IL-27Rα/gp130 receptor. [4] Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4 + and CD8 + T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses.…”

“…[4] IL-27 is a heterodimeric cytokine composed of the subunits p28 and EBI3, which bind to the heterodimeric IL-27Rα/gp130 receptor. [4] Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4 + and CD8 + T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Xia et al provide evidence that IL-27 acts as a pathogenic pro-inflammatory cytokine and upregulate CD4 + Foxp3 + Tregs production during the CD4 + T-cell mediated immunity against HSV-1, which ultimately resulted in promoting the progression of HSK and poor prognosis.…”