Interaction of high-mobility group box 1-mediated activation of eosinophils with dermal fibroblasts: implication of damaging inflammation in atopic dermatitis
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香港中文大學研究人員

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摘要Background: Atopic dermatitis (AD) is a widely prevalent and chronically relapsing inflammatory skin disease. A skin-lesion-related prototypical damage-associated molecular pattern (DAMP) high mobility group box 1 (HMGB1) is a DNA-binding nuclear cytokine which can be released passively during cell necrosis, which is known to be implicated in allergic diseases, through binding to the receptor for advanced glycation end products.

Methodology: In the present study, we evaluate the plasma concentration of HMGB1 in AD patients and control subjects using ELISA. In vitro co-culture of primary human peripheral blood eosinophils and dermal fibroblasts together with AD mice model were used to elucidate the cellular mechanisms of damaging inflammation in AD.

Results: Significantly elevated plasma concentration of HMGB1 was demonstrated in AD patients when compared to sex- and age-matched normal control subjects (p = 0.0003), and RAGE expression was confirmed on eosinophils and basophils. Using our established MC903-induced AD-like mouse model, both eosinophils and basophils, the principal effector cells in allergic inflammation, have been found to infiltrate into the dermal layer. The i.p. injection of depleting antibodies MAR-1 and TRFK5 drastically eliminated circulating basophils and eosinophils, respectively and subsequently reduced the induced increment of ear thicknesses in AD mice. The i.p. injection of anti-HMGB1 antibody alleviated the MC903-induced AD-like symptoms in mice. HMGB1 could induce the dose-dependent release of IL-6 and chemokine CXCL8 and CCL4 from eosinophils and co-culture of eosinophils and dermal fibroblasts. Co-culture exhibited a synergistic induction of AD-related inflammatory IL-6 upon HMGB1 activation compared to eosinophils and dermal fibroblasts alone. HMGB1 could activate the intracellular nuclear factor (NF)-B pathway in eosinophils of co-culture with dermal fibroblasts. Inhibitor for p38 mitogen-activated protein kinase and NF-kB could significantly suppress HMGB1-mediated AD-related cytokine and chemokine production in co-culture of eosinophils and dermal fibroblasts (all p < 0.05).

Conclusion: Together, the above clinical, in vitro and in vivo result have confirmed HMGB1 is the novel and crucial DAMP molecule linking the tissue-damage-mediated innate immune response with the subsequent allergic inflammation through the activation of eosinophils/basophils and dermal fibroblasts, via distinct intracellular signaling mechanisms.
著者CK Wong, IMT Chu, D Jiao, MSM Tsang, J Zhu, CWK Lam
會議名稱The 10th Hong Kong Allergy Convention
會議開始日29.09.2018
會議完結日30.09.2018
會議地點Hong Kong
會議國家/地區香港
出版年份2018
月份9
日期29
語言英式英語

上次更新時間 2019-07-01 於 14:54