title: CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway.
abstract: Collaboration between heterogeneous pattern recognition receptors (PRRs) leading to synergistic coordination of immune response is important for the host to fight against invading pathogens. Although complement receptor 3 (CR3) and Dectin-1 are major PRRs to detect fungi, crosstalk between these two receptors in antifungal immunity is largely undefined. Here we took advantage of Histoplasma capsulatum which is known to interact with both CR3 and Dectin-1 and specific particulate ligands to study the collaboration of CR3 and Dectin-1 in macrophage cytokine response. By employing Micro-Western Array (MWA), genetic approach, and pharmacological inhibitors, we demonstrated that CR3 and Dectin-1 act collaboratively to trigger macrophage TNF and IL-6 response through signaling integration at Syk kinase, allowing subsequent enhanced activation of Syk-JNK-AP-1 pathway. Upon engagement, CR3 and Dectin-1 colocalize and form clusters on lipid raft microdomains which serve as a platform facilitating their cooperation in signaling activation and cytokine production. Furthermore, in vivo studies showed that CR3 and Dectin-1 cooperatively participate in host defense against disseminated histoplasmosis and instruct adaptive immune response. Taken together, our findings define the mechanism of receptor crosstalk between CR3 and Dectin-1 and demonstrate the importance of their collaboration in host defense against fungal infection.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Juin-Hua
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Chu
authors.affiliation: Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Wu-Hsieh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006658:Histoplasma; D006660:Histoplasmosis / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D034741:RNA, Small Interfering; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D018808:Transcription Factor AP-1 / Q000276:immunology; D014162:Transfection; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D048670:MAP Kinase Kinase 4; D016177:Macrophage-1 Antigen; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000072377:Syk Kinase; D018808:Transcription Factor AP-1; D000099181:Dectin-1; C000606897:Syk protein, mouse