title: An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells.
abstract: A variety of reactive organic compounds, called haptens, can cause allergic contact dermatitis. However, the innate immune mechanisms by which haptens stimulate dendritic cells (DCs) to sensitize T cells remain unclear. Here we show that the coupling of ITAM-Syk-CARD9 signalling to interleukin-1 (IL-1) secretion in DCs is crucial for allergic sensitization to haptens. Both MyD88 and Caspase recruitment domain-containing protein 9 (CARD9) signalling are required for contact hypersensitivity (CHS). Naïve T cells require signals received through IL-1R1-MyD88 for effector differentiation, whereas DCs require CARD9 and spleen tyrosine kinase (Syk) signalling for hapten-induced IL-1α/β secretion and their ability to prime T cells. DC-specific deletion of CARD9, DAP12, Syk or NLRP3, but not MyD88, is sufficient to abolish CHS. All tested haptens, but not irritants, can induce Syk activation, leading to both the CARD9/BCL10-dependent pro-IL-1 synthesis (signal1) and reactive oxygen species-mediated NLRP3 inflammasome activation (signal2), required for IL-1 secretion. These data unveil an innate immune mechanism crucial for allergic contact sensitization to chemical compounds.
authors.affiliation: 1] Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan [2] Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yasukawa
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Yoshii
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.affiliation: 1] Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan [2] Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim, 6-7-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Pathology and Biodefense, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Toda
authors.affiliation: Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (IFREC), Osaka University, 3-1 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.affiliation: Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Laboratory for Lymphocyte Differentiation, RIKEN Reserach Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Kanagawa, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara Sakyo, Kyoto 606-8507, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Natsuaki
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Mi-ichi
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Ei'ichi
authors.initials: E
authors.lastname: Iizasa
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakahara
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara Sakyo, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kabashima
authors.affiliation: Division of Laboratory Animal, Research Institute for Biomedical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda 278-0022, Chiba, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Miyagi, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.affiliation: Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: 1] Laboratory for Lymphocyte Differentiation, RIKEN Reserach Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Kanagawa, Japan [2] Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center (iFREC), Osaka University, 3-1 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Parc Scientifique de Marseille-Luminy, Marseille Cedex 9 13288, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392, Tokyo, Japan.
authors.forename: Naohito
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000072377:Syk Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D002352:Carrier Proteins; C583355:IL1R1 protein, mouse; D058847:Inflammasomes; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D053573:Receptors, Interleukin-1 Type I; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D020170:Caspase 1