Type II cytokines impair host defense against an intracellular fungal pathogen by amplifying macrophage generation of IL-33

Abstract

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.

Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity

“…IL-33 generation in antigen-presenting cells can be induced by multiple stimuli such as influenza virus (18), Nippostrongylus Brasiliensis (47), Histoplasma capsulatum (48), and TLR agonists (49), and prior studies have demonstrated roles for both interferon regulatory factors (IRFs) and NF-κB in the transcriptional regulation of IL-33. IRF3 is required for TLR3 and TLR4-induced IL-33 in murine macrophages (49), and IRF4 is required for both Dectin-1 and Dectin-2-induced IL-33 in macrophages and DCs, respectively (48, 50). However, NF-κB is required for TLR5-induced IL-33 generation from murine DCs (51) and for TLR3 and TLR5-induced IL-33 from human epithelial cells (52).…”

Histoplasma Capsulatum , Lung Infection and Immunity

“…CCR2 KO mice also exhibit increased IL-4 production and impaired clearance [64]. In these mice IL-4 triggers production of another Th2-associated cytokine, IL-33, by infected macrophages [65]. Subsequent to these elevated cytokines, a shift to the maladaptive M2 macrophage phenotype occurs.…”

Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands

“…Increased IL-4 in Ccr2 −/− mice led to alternative activation of alveolar and tissue macrophages resulting in impaired fungal clearance. In fact, a recent study by the Deepe group showed that IL-4 acts in synergy with Histoplasma to amplify IL-33 production by macrophages via STAT-6/IRF-4 and dectin-1 signaling [113]. In turn, IL-33–primed macrophages are permissive for increased intracellular fungal growth and survival, and neutralization of IL-33 in Ccr2 −/− mice restores host resistance during histoplasmosis [113].…”

“…In fact, a recent study by the Deepe group showed that IL-4 acts in synergy with Histoplasma to amplify IL-33 production by macrophages via STAT-6/IRF-4 and dectin-1 signaling [113]. In turn, IL-33–primed macrophages are permissive for increased intracellular fungal growth and survival, and neutralization of IL-33 in Ccr2 −/− mice restores host resistance during histoplasmosis [113]. The source of IL-4 in the lungs of Ccr2 −/− mice is both mononuclear phagocytes (macrophages and DCs) [112] and CD4 + T cells [114].…”