Abstract
Purpose :
The recently discovered interleukin (IL) -36 (α, β, γ, and Ra) are the members of the IL-1 superfamily of cytokines. While the IL-1 subfamily has been extensively studied, the role of IL-36 in the pathogenesis of infection diseases is understudied. In this study, we sought to determine if and how IL-36γ regulates innate immunity against Candida Albians (CA).
Methods :
The wildtype C57BL/6 mice, IL-36γ knock-out B6 mice, and subconjunctival injection of mouse recombinant IL-36γ were used to determine the effects of IL-36γ on the severity of fungal keratitis. The parameters assessed included clinical scoring, photographing of infected corneas, fungal plate counting, and MPO assay. Quantitative real-time PCR, Western blot, ELISA and immunohistochemistry were used to assess the effects of IL-36γ on the expression/production of cytokines, chemokines, cyto-protective genes and antimicrobial peptides.
Results :
The expression of IL-36α, β, γ, and Ra were elevated in the cornea in response to CA infection. IL-36 receptor (IL-36R) was detected in normal and its expression was significantly increased in the epithelium as well as in CD11c positive cells in infected corneas at 1 dpi. Compared to the wildtype, IL-36γKO mice have more severe keratitis with higher fungal burden, MPO level, IL-1β expression and lower levels of IL-1Ra, AMPs. Infected IL-36γKO corneas at 1 dpi also had less DCs, macrophages, γδT cells, and NK cells, which formed clusters at difference parts of corneas with necrosis. Treatment with IL-36γ, on the other hand, greatly reduced severity of CA keratitis and elevated expression of CCL3, CCL5, S100A8/9, and IL-1Ra. IL-36γ treatment without infection recruited DCs, macrophage, γδT cells, and NK cells underneath the epithelium. IL-36γ pre-treated corneas had elevated expression of HSP90AB1, ICAM1, OAS2, and TNFαIP3 which were further augmented by CA infection.
Conclusions :
IL-36γ can induce anti-fungal immunity against CA including induction of innate immune cell infiltration and enhancing the expression of cyto-protective genes, antimicrobial peptides, anti-inflammatory cytokines, and chemokines in the cornea.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.