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. Access through your institution Buy or subscribe This is a preview of

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James J. Lee from the Mayo Clinic (Scottsdale, AZ, USA) for providing us the rat anti-mouse MBP antibody. This work was supported by the Research Grant Committee General Research Fund, Hong

Kong (project reference no.: CUHK 476813, principal investigator: CKW). AUTHOR INFORMATION Author notes * Delong Jiao and Chun-Kwok Wong: Delong Jiao and Chun-Kwok Wong share first

authorship on this article. AUTHORS AND AFFILIATIONS * Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China Delong

Jiao, Chun-Kwok Wong, Huai-Na Qiu, Jie Dong, Zhe Cai, Man Chu, Miranda Sin-Man Tsang & Christopher Wai-Kei Lam * 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 Chun-Kwok Wong & Miranda Sin-Man Tsang * Department of Paediatrics, The Chinese University of

Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China Kam-Lun Hon * 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 Christopher Wai-Kei Lam Authors * Delong Jiao View author publications You can also

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Christopher Wai-Kei Lam View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Chun-Kwok Wong. ETHICS DECLARATIONS

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ABOUT THIS ARTICLE CITE THIS ARTICLE Jiao, D., Wong, CK., Qiu, HN. _et al._ NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts

in atopic dermatitis-like skin inflammation. _Cell Mol Immunol_ 13, 535–550 (2016). https://doi.org/10.1038/cmi.2015.77 Download citation * Received: 18 March 2015 * Revised: 16 July 2015 *

Accepted: 17 July 2015 * Published: 21 September 2015 * Issue Date: July 2016 * DOI: https://doi.org/10.1038/cmi.2015.77 SHARE THIS ARTICLE Anyone you share the following link with will be

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initiative KEYWORDS * atopic dermatitis * basophils, eosinophils * NOD2 * TLR2