DCs are known as the main target of TSLP
47 and TSLP acts as a link between epithelial cells and DCs.
48,49 In the current study, we showed that DCs expressed TSLPR in the cornea. Using a well-established transgenic mouse line, we transiently depleted DCs and showed that DC depletion resulted in a much more severe keratitis. This result is in sharp contrast of a report that showed temporary depletion of CD11c positive cells triggered phagocyte accumulation in the spleen and enhances their innate bacterial killing capacity in an experimental infection model of
Yersinia enterocolitica, a bacterium that causes food-borne acute and chronic gastrointestinal and systemic diseases in both humans and mice.
50 The ablation of DCs was also shown to enhance resistance to intranasal challenge with
Pneumococcal pneumonia.
51 As an immune privileged site, DCs are the only immune cells residing in the corneal epithelium, which lacks γδ-T cells,
52 while macrophages are present in the posterior corneal stroma.
53 The infiltrated γδ T cells were shown to directly stimulate epithelial secretion of CXCL1, a chemokine that promotes recruitment of neutrophils
54,55 and promotes a IL-17 response at the ocular surface.
56 Hence, lack of DCs may lead to the deficiency of the timely infiltration of γδ T cell from the limbal region, resulting in delayed PMN infiltration, and the deficiency of IL-17 responses in the cornea,
57 resulting in its rapid clinical deterioration as seen at 3 dpi of DC-depleted corneas (
Fig. 7). Indeed, unlike in TSLPR-neutralized corneas, DC-depletion resulted in the suppression of both IL-17A and 17C, although levels of TSLP and IL-23 was not affected. Although DCs are thought to be the major source of IL-23, it can also be produced by epithelial cells in response to injury, allergic challenge, and infection.
58–60 This may explain why a high level of IL-23 mRNA was detected in DC-depleted corneas. Our study is the first to link DCs in an infected tissue to the expression of IL-17 isoforms. It is important to note that the majority of IL-17 is associated with cells of the innate immune system such as neutrophils, γδT cells, and innate lymphoid cells
61 and that epithelia express and secrete IL-23 to regulate intestinal epithelial cell homeostasis to limit mucosal damage.
60 The function of IL-17 as a whole, and of the individual isoforms IL-17A and IL-17C in the pathogenesis of
P. aeruginosa keratitis is currently under investigation in our laboratory.