Type II Cytokines Impair Host Defense Against Intracellular Fungal Pathogen by Amplifying Macrophage Generation of IL-33

IL-4 subverts protective immunity to multiple intracellular pathogens including the fungus Histoplasma capsulatum. Previously, we reported that H. capsulatum-challenged CCR2(−/−) mice manifest elevated pulmonary fungal burden due to exaggerated IL-4. Paradoxical to our anticipation in IL-33 driving IL-4, we discovered the latter prompted IL-33 in mutant mice. In infected CCR2(−/−) animals, amplified IL-33 succeeded the heightened IL-4 response and inhibition of IL-4 signaling decreased IL-33. Moreover, macrophages, but not epithelial cells or dendritic cells from these mice expressed higher IL-33 in comparison to controls. Dissection of mechanisms that promulgated IL-33 revealed type-II cytokines and H. capsulatum synergistically elicited an IL-33 response in macrophages via STAT6/IRF-4 and Dectin-1 pathways respectively. Neutralizing IL-33 in CCR2(−/−) animals, but not controls, enhanced their resistance to histoplasmosis. Thus, we describe a previously unrecognized role for IL-4 in instigating IL-33 in macrophages. Furthermore, in presence of intracellular fungal pathogens, the type-II cytokine-driven IL-33 response impairs immunity.