title: JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression.
abstract: Opportunistic fungal infections are a leading cause of death among immune-compromised patients, and there is a pressing need to develop new antifungal therapeutic agents because of toxicity and resistance to the antifungal drugs currently in use. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host antifungal immunity, little is known about the mechanisms that negatively regulate host immune responses to a fungal infection. Here we found that JNK1 activation suppresses antifungal immunity in mice. We showed that JNK1-deficient mice had a significantly higher survival rate than wild-type control mice in response to Candida albicans infection, and the expression of JNK1 in hematopoietic innate immune cells was critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 gene promoter. Blocking either CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response found in JNK1-deficient mice. Notably, JNK inhibitors exerted potent antifungal therapeutic effects in both mouse and human cells infected with C. albicans, indicating that JNK1 may be a therapeutic target for treating fungal infection.
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Xueqiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Changying
authors.identifier: http://orcid.org/0000-0003-3778-4438
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Immunology, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Tianming
authors.initials: T
authors.lastname: Luo
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Jia
authors.affiliation: Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Institute for Immunology, Tsinghua University School of Medicine, Beijing, China.|Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D002176:Candida albicans; D002177:Candidiasis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D015151:Immunoblotting; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D041681:NIH 3T3 Cells; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics* / Q000276:immunology
chemical_list: D016207:Cytokines; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D017455:Receptors, IgE; D009569:Nitric Oxide; D048055:Mitogen-Activated Protein Kinase 8