Topical Neutralization of Interleukin-17 during Experimental Pseudomonas aeruginosa Corneal Infection Promotes Bacterial Clearance and Reduces Pathology

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The proinflammatory cytokine interleukin-17 (IL-17) is involved in neutrophilic tissue infiltration, contributing to both microbial clearance as well as inflammation-associated tissue damage. Its role during bacterial corneal infections is unknown. We hypothesized that IL-17 responses would be detrimental in this setting and tested the impact of IL-17 receptor deficiency or antibody-mediated neutralization of IL-17 in a murine model of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Pseudomonas aeruginosa</jats:named-content>ulcerative keratitis after scratch injury. We found that, compared with infected corneas from wild-type mice, those from IL-17 receptor (IL-17R)-deficient mice had significantly lower corneal pathology scores, neutrophil influx, and intracellular bacterial levels. Infected IL-17R-deficient corneas had low intercellular adhesion molecule 1 (ICAM-1) expression, and ICAM-1-deficient mice were similarly resistant to infection. Topical treatment with polyclonal antibodies to IL-17 resulted in significant reductions in corneal pathology and also lowered bacterial counts after infection with six different laboratory or clinical<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. aeruginosa</jats:named-content>strains, including both invasive and cytotoxic strains. Thus, neutralization of IL-17 during<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. aeruginosa</jats:named-content>corneal infection reduces neutrophil influx and pathology without compromising bacterial clearance and offers a promising new avenue for therapy of these potentially sight-threatening infections.</jats:p>

Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

“…The findings here with S. aureus are, however, distinct from those with P. aeruginosa corneal infection, where loss of IL-17 activity actually reduced the consequences of P. aeruginosa corneal infection in nonimmune mice (40). For further perspective, IL-17 production by ␥␦ T cells has been shown to be important for resistance to S. aureus surgical-site infections (41,42), but neutralization of IL-17A in BALB/c mice did not affect the response to a primary S. aureus dermonecrotic skin infection (43).…”

“…Notably, these cells are present in RAG KO mice and produce IL-17 and IL-22 in response to zymosan injection (44), but the lack of effectiveness of antibody in the RAG KO mice indicates that the cytokines are not sufficient by themselves to mediate antibody-based protective immunity in the eye. Additionally, we have previously shown that IL-17R KO mice are also deficient in ICAM-1, which we previously associated with the improved outcome from P. aeruginosa keratitis due to decreased corneal pathology without impact on bacterial clearance (40). However, in order for antibody-mediated immunity to be effective against bacterial pathogens such as P. aeruginosa and S. aureus, PMN-mediated opsonic killing is required (45,46).…”

Interleukin 17 Regulates Mer Tyrosine Kinase-Positive Cells in Pseudomonas aeruginosa Keratitis

“…24,25 It has been reported that IL-17 is produced in cornea during P. aeruginosa keratitis. 9 Results presented in this study revealed that IL-17 was not detected in normal cornea and that after P. aeruginosa infection its expression is disparately upregulated in C57BL/6 (more) versus BALB/c (less) corneas. These data, suggesting a potential role for IL-17 in the development of susceptible versus resistant phenotype, are consistent with results in a previous study 25 from another laboratory showing that P. aeruginosa keratitis induced a strong Th17 cell response in C57BL/6 mice that results in IL-17 production in cornea.…”

“…Previous investigations have shown that topical IL-17 neutralization reduces corneal pathology, PMN influx, and intracellular bacterial levels and improves early outcome for P. aeruginosa keratitis in C57BL/6 mice. 9 Neutralization of IL-17 also reduces the corneal lesion severity in recurrent herpetic keratitis in BALB/c mice. 10 Furthermore, Candida keratitis development was blocked after neutralization of IL-17 activity in BALB/c mice.…”

γδ T cells regulate the expression of cytokines but not the manifestation of fungal keratitis

“…In the Aspergillus fumigates infected lung, CXCR2 recruits neutrophils to the infection site (Bonnett et al, 2006). In the cornea, ICAM-1, MIP-2 and other cytokines have a role in attracting neutrophils to the inflammatory site (Gagen et al, 2010;Zaidi et al, 2012;Tripathi et al, 2013). However, the regulator of neutrophil infiltration in FK is unknown.…”