title: NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation.
abstract: The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD.
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Delong
authors.initials: D
authors.lastname: Jiao
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.|Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chun-Kwok
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Huai-Na
authors.initials: HN
authors.lastname: Qiu
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Man
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Kam-Lun
authors.initials: KL
authors.lastname: Hon
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.|Institute of Chinese Medicine and State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Miranda Sin-Man
authors.initials: MS
authors.lastname: Tsang
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.|State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, People's Republic of China.
authors.forename: Christopher Wai-Kei
authors.initials: CW
authors.lastname: Lam
mesh_terms: D000818:Animals; D001491:Basophils / Q000276:immunology*; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D004804:Eosinophils / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D013211:Staphylococcus aureus / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D008024:Ligands; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D051195:Toll-Like Receptor 2; D018799:Intercellular Adhesion Molecule-1