title: Type II cytokines impair host defense against an intracellular fungal pathogen by amplifying macrophage generation of IL-33.
abstract: Interleukin (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 owing to exaggerated IL-4. Paradoxical to our anticipation in IL-33 driving IL-4, we discovered that 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 with controls. Dissection of mechanisms that promulgated IL-33 revealed type-II cytokines and H. capsulatum synergistically elicited an IL-33 response in macrophages via signal transducer and activator of transcription factor 6/interferon-regulatory factor-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 the presence of intracellular fungal pathogens, the type-II cytokine-driven IL-33 response impairs immunity.
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA [2] Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: A
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Kroetz
authors.affiliation: 1] Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA [2] Department of Pathobiology and Molecular Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Tweedle
authors.affiliation: 1] Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA [2] Veterans Affairs Hospital, Cincinnati, Ohio, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D005658:Fungi / Q000276:immunology*; D015870:Gene Expression; D054884:Host-Pathogen Interactions / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000099218:Interferon Regulatory Factor-4; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; D000067596:Interleukin-33; D007378:Interleukins; D037181:Lectins, C-Type; D054390:Receptors, CCR2; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D000099218:Interferon Regulatory Factor-4; D000099181:Dectin-1; C506535:Il33 protein, mouse