How might IL-36R mediate the innate immune response to
CA infection? Various studies have shown that IL-36R activation induces the release of antimicrobial proteins such as human beta-defensins 2 and 3, LL37, S100A7, and more importantly S100A8/A9.
30,47–49 In an oral candidiasis model, IL-36R
−/− mice show an increased fungal burden and reduced IL-23 gene expression.
9,10,26,50 Previously, we found that IL-36R antagonist (IL-36Ra) downregulation and exogenous IL-36γ prevented corneal infection while exogenous IL-36Ra augmented the pathogenesis of
P. aeruginosa-keratitis.
11 Our current study provides evidence that IL-36R signaling influences the outcome of
CA keratitis by suppressing the expression of proinflammatory cytokines IL-1β and promoting the expression of IL-Ra, S100A8, and S100A9. Furthermore, our data show that IL-36R deficiency enhanced innate immune defense and reduced severity of
CA keratitis. IL-36γ-deficient mice infected with
Streptococcus pneumoniae exhibited diminished lung bacterial clearance, increased bacterial dissemination and a higher mortality rate.
26,51 Our results are consistent with the protective role of IL-36γ in corneal innate defense against fungal infection. IL-36γ significantly stimulates the expression of S100A8, S100A9, and sIL-1RA, but not IL-1β, in uninfected corneas in vivo. To our knowledge, this is the first report of IL-36-stimulated upregulation of S100A8/A9 or calprotectin in a mucosal surface with or without infection. Because calprotectin possesses potent anti-
CA activity,
30–32 its upregulation may represent an underlying mechanism for IL-36/IL-36R to play a protective role in
CA keratitis. Although the activation of IL-1β, a master pro-inflammatory cytokine, is most stringently regulated, its final activities are likely determined by the ratio of IL-1β/sIL-1Ra.
52–54 Hence, the differential effects of IL-36γ on the expression of IL-1β and sIL-1Ra in naïve and infected corneas is consistent with our recently-suggested notion that the IL-36 family of cytokines, as a whole, antagonize IL-1R in the corneas in response to microbial infection. Because blocking IL-1R activation has been used to treat a broad spectrum of diseases, such as gout, rheumatoid arthritis, type 2 diabetes, atherosclerosis, and acute myocardial infarction,
55 activation of IL-36R signaling may have syngeneic effects with Anakinra, a human recombinant IL-1Ra clinically used to treat aforementioned inflammatory diseases,
56 as well as COVID-19.
57,58