Toll-like receptor 2-expressing macrophages are required and sufficient for rhinovirus-induced airway inflammation

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• 作者：Mingyuan Han ; PhD^a ; ^&lowast ; ; Yutein Chung ; PhD^a ; ^&lowast ; ; Jun Young Hong ; PhD^b ; Charu Rajput ; PhD^a ; Jing Lei ; BS^a ; Joanna L. Hinde ; MS^a ; Qiang Chen ; BS^a ; Steven P. Weng ; BS^a ; J. Kelley Bentley ; PhD^a ; Marc B. Hershenson ; MD^a ; ^b ; ^{mhershen@umich.edu}
• 关键词：Alternative activation ; asthma ; CD11b ; exacerbation ; M2 macrophage
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：138
• 期：6
• 页码：1619-1630
• 全文大小：2734 K
• 卷排序：138

文摘

We have shown that rhinovirus, a cause of asthma exacerbation, colocalizes with CD68+ and CD11b+ airway macrophages after experimental infection in human subjects. We have also shown that rhinovirus-induced cytokine expression is abolished in Toll-like receptor (TLR2)−/− bone marrow–derived macrophages.ObjectiveWe hypothesize that TLR2+ macrophages are required and sufficient for rhinovirus-induced airway inflammation in vivo.MethodsNaive and ovalbumin (OVA)–sensitized and challenged C57BL/6 wild-type and TLR2−/− mice were infected with RV1B, followed by IgG or anti-TLR2, to determine the requirement and sufficiency of TLR2 for rhinovirus-induced airway responses. Bone marrow chimera experiments using OVA-treated C57BL/6 and TLR2−/− mice were also performed. Finally, naive TLR2−/− mice underwent intranasal transfer of bone marrow–derived wild-type macrophages.ResultsRV1B infection of naive wild-type mice induced an influx of airway neutrophils and CD11b+ exudative macrophages, which was reduced in TLR2−/− mice. After allergen exposure, rhinovirus-induced neutrophilic and eosinophilic airway inflammation and hyperresponsiveness were reduced in TLR2−/− and anti-TLR2–treated mice. Transfer of TLR2−/− bone marrow into wild-type, OVA-treated C57BL/6 mice blocked rhinovirus-induced airway responses, whereas transfer of wild-type marrow to TLR2−/− mice restored them. Finally, transfer of wild-type macrophages to naive TLR2−/− mice was sufficient for neutrophilic inflammation after rhinovirus infection, whereas macrophages treated with IL-4 (to induce M2 polarization) were sufficient for eosinophilic inflammation, mucous metaplasia, and airways hyperresponsiveness.ConclusionsTLR2 is required for early inflammatory responses induced by rhinovirus, and TLR2+ macrophages are sufficient to confer airway inflammation to TLR2−/− mice, with the pattern of inflammation depending on the macrophage activation state.