IL-17 Promotes Pseudomonas aeruginosa Keratitis in C57BL/6 Mouse Corneas

Abstract

The aim of this study was to elucidate the expression and functions of IL-17 in C57BL/6 mouse corneas in response to Pseudomonas aeruginosa infection. We found that P. aeruginosa infection induced and increased signaling of IL-23/23R/17/17R in mouse corneas. Targeting IL-17A or the IL-17A-specific receptor IL-17RA/IL-17RC with neutralizing Abs resulted in a significant decrease in the severity of P. aeruginosa keratitis, including a decrease in bacterial burden and polymorphonuclear leukocyte infiltration. IL-17A-signaling blockade also significantly reduced the expression of the proinflammatory cytokines L-1b, IL-24, and MMP-13 and increased the expression of the anti-inflammatory cytokine IL-1RA in mouse corneal epithelium. The presence of mouse IL-17A exacerbated P. aeruginosa-mediated tissue destruction. A cytokine protein array revealed that the expression of osteoprotegerin (OPG) was regulated by IL-17A, and OPG neutralization also resulted in a decrease in the severity of P. aeruginosa keratitis. Although both IL-17 and OPG affected the balanced expression of IL-1b and IL-1RA, only IL-17 inhibited the expression of TH2 cytokines. Taken together, our results revealed that IL-17A, along with its downstream factor OPG, plays a detrimental role in the pathogenesis of P. aeruginosa keratitis. Targeting IL-17A and/or the OPG/RANKL/RANK/TRAIL system is a potential therapeutic strategy in controlling the outcome of P. aeruginosa keratitis, which was demonstrated by concurrent topical application of IL-17A-neutralizing Ab and ciprofloxacin in B6 mice.

Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study

“…Measuring the antibody immune response to infections is a common approach to study this relationship, as seropositivity can both serve as a marker of infection exposure and provide clues about the pathophysiology between infections and NCDs (eg, through molecular mimicry [ 6 ]). This could potentially lead to important diagnostic and therapeutic advances, especially in the fields of vaccination and immunotherapy [ 7–10 ]. Further, given the recent global coronavirus disease 2019 pandemic, understanding immune responses to infection could help to identify common pathways that, when perturbed, influence susceptibility to infection and/or immunological response.…”

Role of TH17 Responses in Increasing Herpetic Keratitis in the Eyes of Mice Infected with HSV-1

“…102 Similar to this study, previously it was shown that IL-17 promotes pseudomonas aeruginosa keratitis in the cornea of infected mice. 103,104 Our eye disease results indicate that the absence of IL17RC is more effective than the absence of IL17A as the IL17RC receptor targets both IL17A and IL17F secretion. Recently, dual inhibition of both IL17A and IL17F in the treatment of psoriatic disease and ankylosing spondylitis was shown to be more effective than single inhibition of each cytokine.…”

“… 102 Similar to this study, previously it was shown that IL-17 promotes pseudomonas aeruginosa keratitis in the cornea of infected mice. 103 , 104 …”

The expression and significance of inflammatory cytokines and MMP-9 in the tears of the infected eye and contralateral uninfected eye in patients with fungal keratitis

“…IL-17 is secreted by Thl7 cells, neutrophils and glial cells can also secrete a few [19]. A large amount of IL-17 expression was found in human cornea with lamentous fungal keratitis [20]. IL-17 can alleviate the severity of fungal keratitis by the expression of CX43 in corneal peripheral vascular endothelial cells [21].…”