title: Pertussis toxin targets the innate immunity through DAP12, FcRγ, and MyD88 adaptor proteins.
abstract: Activation of the innate immunity by adjuvants, such as pertussis toxin (PTX), in the presence of autoreactive lymphocytes and antigen mimicry is sufficient to trigger autoimmunity. Toll-like, C-type lectin, and immunglobulin-like receptors play an important role in the innate immunity by sensing a variety of microbial products through several adaptor proteins, including MyD88, DAP12, and FcRγ. This study investigated the interaction between PTX and innate immune components. The direct interactions between coated PTX and receptor-fusion proteins were examined using ELISA-based binding assays. Functionally, PTX-binding receptors could be classified into two groups: inhibition (DAP12-coupled TREM2, ITIM-bearing SIRPα, SIGNR1/SIGNR3/DCSIGN) and activation (MyD88-associated TLR4, DAP12-coupled LMIR5/CD300b, FcRγ-coupled LMIR8/CD300c, CLEC9A, MGL-1). DAP12, MyD88, and FcRγ were selected for further investigation. A comprehensive analysis of gene transcription showed that PTX up-regulated the expression of various inflammatory mediators. DAP12 deficiency resulted in reduction or enhancement of inflammatory responses in a cytokine-specific manner. PTX was able to activate the TREM2-DAP12 signalling pathway. PTX induced lower expression of inflammatory mediators in the absence of FcRγ alone and substantially lost its inflammatory capacity in the absence of both FcRγ and MyD88. PTX was able to activate the MyD88-NF-κB signalling pathway in the presence of TLR2 or TLR4. The inflammatory activity of PTX was completely lost by heating. These results demonstrate that PTX targets the innate immunity through DAP12, FcRγ, and MyD88 providing new insights into the immunobiology of PTX.
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: contact@mieditor.com.
authors.forename: Vongsavanh
authors.initials: V
authors.lastname: Phongsisay
authors.affiliation: Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors.forename: Ei'ichi
authors.initials: E
authors.lastname: Iizasa
authors.affiliation: Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.affiliation: Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D037342:Pertussis Toxin / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C484963:Tyrobp protein, mouse; D037342:Pertussis Toxin
keywords: Adjuvant; Autoimmunity; Innate immunity; Pertussis toxin; Receptor