M2巨噬细胞可促进童年鼻病毒感染后IL-33表达、ILC2 增殖及黏液化生
2022/09/20
摘要
背景：喘息相关鼻病毒 (RV) 感染与哮喘的发生有关。本团队既往研究已表明，用 RV 感染未成熟小鼠会诱导 2 型细胞因子产生和黏液化生，这依赖于 IL-33 和 2 型先天淋巴细胞 (ILC2s)，并因第二次异源 RV 感染而加剧。本研究假设 M2a巨噬细胞是响应异源 RV 感染的过度炎症和黏液化生所必需的。
方法：对缺乏 M2a 巨噬细胞的野生型 C57Bl/6J 小鼠和 LysMCre IL4Rα KO 小鼠进行如下处理：（1）出生第6天假感染、出生第 13 天假感染，（2）出生第 6 天行RV-A1B感染、出生第 13 天假感染，（3）出生第 6 天假感染、第 13 天RV-A2感染，（4）出生第 6 天 RV-A1B感染、第 13 天 RV-A2感染。
结果：在第二次感染后第1或7 天取肺。第 6 天感染 RV-A1B 的野生型小鼠中表达 Arg1 和 Retnla 的肺巨噬细胞数量增加，提示M2a 极化。与在出生第 6 天和第 13 天感染 RV 的野生型小鼠相比，经异源 RV感染的 LysMCre IL4Rα 敲除小鼠的肺中上皮衍生的先天细胞因子 IL-33、IL-25 和 TSLP 的蛋白质丰度降低，ILC2降低，IL-13 和 IL-5 的 mRNA 表达降低，PAS 染色降低。最后，双重感染的 LysMCre IL4Rα敲除小鼠的 mRNA 分析和免疫荧光显微镜显示气道上皮细胞 IL-33 表达降低，并且用 IL-33 治疗恢复了强化的黏膜炎症表型。
结论：童年RV 感染会改变巨噬细胞对后续异源感染的反应，从而导致 IL-33 表达增强、ILC2 增殖，并加重气道炎症和黏液化生。
M2 Macrophages promote IL-33 expression, ILC2 expansion and mucous metaplasia in response to early life rhinovirus infections.
Han M, Breckenridge HA, Kuo S, Singh S, Goldsmith AG, Li Y, Kreger JE, Bentley JK, Hershenson MB.
Abstract
BACKGROUND:Wheezing-associated rhinovirus (RV) infections are associated with asthma development. We have shown that infection of immature mice with RV induces type 2 cytokine production and mucous metaplasia which is dependent on IL-33 and type 2 innate lymphoid cells (ILC2s) and intensified by a second heterologous RV infection. We hypothesize that M2a macrophages are required for the exaggerated inflammation and mucous metaplasia in response to heterologous RV infection.
METHODS:Wild-type C57Bl/6J mice and LysMCre IL4Rα KO mice lacking M2a macrophages were treated as follows: (1) sham infection on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 and RV-A2 on day 13, or (4) RV-A1B on day 6 and RV-A2 on day 13. Lungs were harvested one or seven days after the second infection.
RESULTS:Wild-type mice infected with RV-A1B at day 6 showed an increased number of Arg1- and Retnla-expressing lung macrophages, indicative of M2a polarization. Compared to wild-type mice infected with RV on day 6 and 13 of life, the lungs of LysMCre IL4Rα KO mice undergoing heterologous RV infection showed decreased protein abundance of the epithelial-derived innate cytokines IL-33, IL-25 and TSLP, decreased ILC2s, decreased mRNA expression of IL-13 and IL-5, and decreased PAS staining. Finally, mRNA analysis and immunofluorescence microscopy of double-infected LysMCre IL4Rα KO mice showed reduced airway epithelial cell IL-33 expression, and treatment with IL-33 restored the exaggerated muco-inflammatory phenotype.
CONCLUSIONS:Early-life RV infection alters the macrophage response to subsequent heterologous infection, permitting enhanced IL-33 expression, ILC2 expansion and intensified airway inflammation and mucous metaplasia.
背景：喘息相关鼻病毒 (RV) 感染与哮喘的发生有关。本团队既往研究已表明，用 RV 感染未成熟小鼠会诱导 2 型细胞因子产生和黏液化生，这依赖于 IL-33 和 2 型先天淋巴细胞 (ILC2s)，并因第二次异源 RV 感染而加剧。本研究假设 M2a巨噬细胞是响应异源 RV 感染的过度炎症和黏液化生所必需的。
方法：对缺乏 M2a 巨噬细胞的野生型 C57Bl/6J 小鼠和 LysMCre IL4Rα KO 小鼠进行如下处理：（1）出生第6天假感染、出生第 13 天假感染，（2）出生第 6 天行RV-A1B感染、出生第 13 天假感染，（3）出生第 6 天假感染、第 13 天RV-A2感染，（4）出生第 6 天 RV-A1B感染、第 13 天 RV-A2感染。
结果：在第二次感染后第1或7 天取肺。第 6 天感染 RV-A1B 的野生型小鼠中表达 Arg1 和 Retnla 的肺巨噬细胞数量增加，提示M2a 极化。与在出生第 6 天和第 13 天感染 RV 的野生型小鼠相比，经异源 RV感染的 LysMCre IL4Rα 敲除小鼠的肺中上皮衍生的先天细胞因子 IL-33、IL-25 和 TSLP 的蛋白质丰度降低，ILC2降低，IL-13 和 IL-5 的 mRNA 表达降低，PAS 染色降低。最后，双重感染的 LysMCre IL4Rα敲除小鼠的 mRNA 分析和免疫荧光显微镜显示气道上皮细胞 IL-33 表达降低，并且用 IL-33 治疗恢复了强化的黏膜炎症表型。
结论：童年RV 感染会改变巨噬细胞对后续异源感染的反应，从而导致 IL-33 表达增强、ILC2 增殖，并加重气道炎症和黏液化生。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Front Immunol. 2022 Aug 12;13:952509. doi: 10.3389/fimmu.2022.952509.)
(Front Immunol. 2022 Aug 12;13:952509. doi: 10.3389/fimmu.2022.952509.)
M2 Macrophages promote IL-33 expression, ILC2 expansion and mucous metaplasia in response to early life rhinovirus infections.
Han M, Breckenridge HA, Kuo S, Singh S, Goldsmith AG, Li Y, Kreger JE, Bentley JK, Hershenson MB.
Abstract
BACKGROUND:Wheezing-associated rhinovirus (RV) infections are associated with asthma development. We have shown that infection of immature mice with RV induces type 2 cytokine production and mucous metaplasia which is dependent on IL-33 and type 2 innate lymphoid cells (ILC2s) and intensified by a second heterologous RV infection. We hypothesize that M2a macrophages are required for the exaggerated inflammation and mucous metaplasia in response to heterologous RV infection.
METHODS:Wild-type C57Bl/6J mice and LysMCre IL4Rα KO mice lacking M2a macrophages were treated as follows: (1) sham infection on day 6 of life plus sham on day 13 of life, (2) RV-A1B on day 6 plus sham on day 13, (3) sham on day 6 and RV-A2 on day 13, or (4) RV-A1B on day 6 and RV-A2 on day 13. Lungs were harvested one or seven days after the second infection.
RESULTS:Wild-type mice infected with RV-A1B at day 6 showed an increased number of Arg1- and Retnla-expressing lung macrophages, indicative of M2a polarization. Compared to wild-type mice infected with RV on day 6 and 13 of life, the lungs of LysMCre IL4Rα KO mice undergoing heterologous RV infection showed decreased protein abundance of the epithelial-derived innate cytokines IL-33, IL-25 and TSLP, decreased ILC2s, decreased mRNA expression of IL-13 and IL-5, and decreased PAS staining. Finally, mRNA analysis and immunofluorescence microscopy of double-infected LysMCre IL4Rα KO mice showed reduced airway epithelial cell IL-33 expression, and treatment with IL-33 restored the exaggerated muco-inflammatory phenotype.
CONCLUSIONS:Early-life RV infection alters the macrophage response to subsequent heterologous infection, permitting enhanced IL-33 expression, ILC2 expansion and intensified airway inflammation and mucous metaplasia.
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儿童肥胖相关哮喘CD4+T细胞与气道平滑肌的相互作用
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局部 IL-10 替代疗法对小鼠的类固醇不敏感哮喘有效
