title: Dendritic cell-derived nitric oxide inhibits the differentiation of effector dendritic cells.
abstract: Dendritic cells (DCs) play a pivotal role in the development of effective immune defense while avoiding detrimental inflammation and autoimmunity by regulating the balance of adaptive immunity and immune tolerance. However, the mechanisms that govern the effector and regulatory functions of DCs are incompletely understood. Here, we show that DC-derived nitric oxide (NO) controls the balance of effector and regulatory DC differentiation. Mice deficient in the NO-producing enzyme inducible nitric oxide synthase (iNOS) harbored increased effector DCs that produced interleukin-12, tumor necrosis factor (TNF) and IL-6 but normal numbers of regulatory DCs that expressed IL-10 and programmed cell death-1 (PD-1). Furthermore, an iNOS-specific inhibitor selectively enhanced effector DC differentiation, mimicking the effect of iNOS deficiency in mice. Conversely, an NO donor significantly suppressed effector DC development. Furthermore, iNOS-/- DCs supported enhanced T cell activation and proliferation. Finally iNOS-/- mice infected with the enteric pathogen Citrobacter rodentium suffered more severe intestinal inflammation with concomitant expansion of effector DCs in colon and spleen. Collectively, our results demonstrate that DC-derived iNOS restrains effector DC development, and offer the basis of therapeutic targeting of iNOS in DCs to treat autoimmune and inflammatory diseases.
authors.affiliation: Institute of Immunology and Molecular Medicine, Jining Medical College, Shandong 272067, China.
authors.forename: Chuanping
authors.initials: C
authors.lastname: Si
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Geming
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Institute of Immunology and Molecular Medicine, Jining Medical College, Shandong 272067, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Feihong
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wei
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Institute of Immunology, Taishan Medical University, Tai'an, Shandong 271000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Garabet
authors.initials: G
authors.lastname: Yeretssian
authors.affiliation: Institute of Immunology and Molecular Medicine, Jining Medical College, Shandong 272067, China.|Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D007113:Immunity, Innate / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: dendritic cell; iNOS