title: JAK/STAT regulation of Aspergillus fumigatus corneal infections and IL-6/23-stimulated neutrophil, IL-17, elastase, and MMP9 activity.
abstract: IL-6 and IL-23 (IL-6/23) induce IL-17A (IL-17) production by a subpopulation of murine and human neutrophils, resulting in autocrine IL-17 activation, enhanced production of reactive oxygen species, and increased fungal killing. As IL-6 and IL-23 receptors trigger JAK1, -3/STAT3 and JAK2/STAT3 phosphorylation, respectively, we examined the role of this pathway in a murine model of fungal keratitis and also examined neutrophil elastase and gelatinase (matrix metalloproteinase 9) activity by IL-6/23-stimulated human neutrophils in vitro. We found that STAT3 phosphorylation of neutrophils in Aspergillus fumigatus-infected corne as was inhibited by the JAK/STAT inhibitor Ruxolitinib, resulting in impaired fungal killing and decreased matrix metalloproteinase 9 activity. In vitro, we showed that fungal killing by IL-6/23-stimulated human peripheral blood neutrophils was impaired by JAK/STAT inhibitors Ruxolitinib and Stattic, and by the retinoic acid receptor-related orphan receptor γt inhibitor SR1001. This was also associated with decreased reactive oxygen species, IL-17A production, and retinoic acid receptor-related orphan receptor γt translocation to the nucleus. We also demonstrate that IL-6/23-activated neutrophils exhibit increased elastase and gelatinase (matrix metalloproteinase 9) activity, which is inhibited by Ruxolitinib and Stattic but not by SR1001. Taken together, these observations indicate that the regulation of activity of IL-17-producing neutrophils by JAK/STAT inhibitors impairs reactive oxygen species production and fungal killing activity but also blocks elastase and gelatinase activity that can cause tissue damage.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Taylor
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and.
authors.forename: Sanhita
authors.initials: S
authors.lastname: Roy
authors.affiliation: School of Medicine, Division of Rheumatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Meszaros
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Howell
authors.affiliation: School of Medicine, Division of Rheumatology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Malemud
authors.affiliation: Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and eric.pearlman@uci.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism*; D007634:Keratitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9
keywords: RORγt; Ruxolitinb; SR1001; Stattic; keratitis