IL-27 limits neutrophil mediated pathology during pulmonary infection with Cryptococcus neoformans

Abstract

Abstract Cryptococcus neoformans is a pathogenic encapsulated fungus and a leading cause of fatal meningitis in immunocompromised individuals. IL-27 is a recently identified cytokine affecting both innate and adaptive immunity. Both proinflammatory and inhibitory functions on T cells by IL-27 have been reported in different disease models. Nevertheless, the effect of IL-27 during Cryptococcus infection has never been studied. In current study, IL-27 receptor alpha knockout mice (IL27R KO) was infected with a high virulent cryptococcal strain. We found that mice deficient in IL-27 signaling have significantly increased fungal burden in the lung and shortened survival time. Surprisingly, infected IL-27R KO mice showed unchanged Th1 and Th17 cytokines but significantly reduced Th2 cytokines including IL-4, IL-5 and IL-13. The reduced Th2 response is unlikely to be a cause of increase fungal burden since Th2 was generally known as detrimental during Cryptococcus infection. We next studied the immune cell composition by flow cytometry, no difference in cell number was found for all cell types except neutrophil which is increased during infection indicating more inflammation. The increase of neutrophils is associated with increased chemokines KC and MIP-2. Cryptococcus infection causes sustained production of TNF alpha, we next found that IL-27 suppressed the chemokine release by immune cells as a response to TNF-alpha. Lastly, depletion of neutrophils improved the outcome in infected IL-27R KO mice proving that immune pathology mediated by neutrophils can be detrimental during Cryptococcus infection.