B细胞衍生的IL-10促进Bcl-3调节的哮喘过敏性增敏
2023/09/21
摘要
空气过敏原致敏主要由肺上皮和树突状细胞介导，是过敏性哮喘发病机制和进展的组成部分。IL-10在免疫反应中具有双重作用，因为它抑制髓细胞活化，但促进B细胞反应和上皮细胞增殖。在此，我们报道了Bcl-3调节的B细胞衍生的IL-10在过敏性哮喘中的促炎功能。具体而言，Bcl-3小鼠表现出IL-10水平升高，并且被发现高度易受屋尘螨（HDMs）诱导的过敏性哮喘的影响。IL-10与HDM致敏小鼠和哮喘患者的DC化学引诱剂CCL-20水平呈正相关，并诱导小鼠肺上皮细胞选择性增加CCL-20的产生。在致敏过程中阻断IL-10或IL-10受体抑制了HDM诱导的致敏和哮喘的发展。IL-10水平在HDM致敏后4小时达到峰值，IL-10主要由B细胞在Bcl-3-Blimp-1-Bcl-6调节下产生。缺乏B细胞衍生的IL-10的小鼠在HDM致敏时表现出肺上皮CCL-20产生减少和DC向肺的募集减少，从而表现出对HDM诱导的哮喘的抵抗力。此外，缺乏B细胞衍生的IL-10的Bcl-3小鼠对HDM刺激的反应与Bcl-3鼠的反应相当。结果揭示了B细胞衍生的IL-10在促进过敏性致敏中的出乎意料的作用，并证明Bcl-3通过抑制B细胞衍生IL-10的产生来预防HDM诱导的哮喘。因此，靶向Bcl-3/IL-10轴抑制过敏性致敏是治疗过敏性哮喘的一种有前途的方法。IL-10在Bcl-3-Blimp-1-Bcl-6调节下在屋尘螨暴露后从肺浆细胞中快速释放，并放大肺上皮细胞（EC）衍生的CCL-20的产生和随后的树突状细胞（DC）募集，以促进哮喘的过敏致敏。
B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3
Guojun Qian, Wenxia Jiang, Donglin Sun, Zhun Sun, Anning Chen, Hongwei Fang, Jingyao Wang, Yongzhong Liu, Zhinan Yin, Haiming Wei, Hao Fang, Xiaoren Zhang
Abstract
Aeroallergen sensitization, mainly mediated by lung epithelium and dendritic cells (DCs), is integral to allergic asthma pathogenesis and progression. IL-10 has a dual role in immune responses, as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation. Here, we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma. Specifically, Bcl-3 mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites (HDMs). IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells. Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development. IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3-Blimp-1-Bcl-6 regulation. Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization, thereby demonstrating resistance to HDM-induced asthma. Moreover, responses to HDM stimulation in Bcl-3 mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3 mice. The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production. Thus, targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma. IL-10 is released rapidly from lung plasma cells under Bcl-3-Blimp-1-Bcl-6 regulation upon house dust mite exposure and amplifies lung epithelial cell (EC)-derived CCL-20 production and subsequent dendritic cell (DC) recruitment to promote allergic sensitization in asthma. -/--/-+/+
空气过敏原致敏主要由肺上皮和树突状细胞介导，是过敏性哮喘发病机制和进展的组成部分。IL-10在免疫反应中具有双重作用，因为它抑制髓细胞活化，但促进B细胞反应和上皮细胞增殖。在此，我们报道了Bcl-3调节的B细胞衍生的IL-10在过敏性哮喘中的促炎功能。具体而言，Bcl-3小鼠表现出IL-10水平升高，并且被发现高度易受屋尘螨（HDMs）诱导的过敏性哮喘的影响。IL-10与HDM致敏小鼠和哮喘患者的DC化学引诱剂CCL-20水平呈正相关，并诱导小鼠肺上皮细胞选择性增加CCL-20的产生。在致敏过程中阻断IL-10或IL-10受体抑制了HDM诱导的致敏和哮喘的发展。IL-10水平在HDM致敏后4小时达到峰值，IL-10主要由B细胞在Bcl-3-Blimp-1-Bcl-6调节下产生。缺乏B细胞衍生的IL-10的小鼠在HDM致敏时表现出肺上皮CCL-20产生减少和DC向肺的募集减少，从而表现出对HDM诱导的哮喘的抵抗力。此外，缺乏B细胞衍生的IL-10的Bcl-3小鼠对HDM刺激的反应与Bcl-3鼠的反应相当。结果揭示了B细胞衍生的IL-10在促进过敏性致敏中的出乎意料的作用，并证明Bcl-3通过抑制B细胞衍生IL-10的产生来预防HDM诱导的哮喘。因此，靶向Bcl-3/IL-10轴抑制过敏性致敏是治疗过敏性哮喘的一种有前途的方法。IL-10在Bcl-3-Blimp-1-Bcl-6调节下在屋尘螨暴露后从肺浆细胞中快速释放，并放大肺上皮细胞（EC）衍生的CCL-20的产生和随后的树突状细胞（DC）募集，以促进哮喘的过敏致敏。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Cell Mol Immunol. 2023 Aug 31. doi: 10.1038/s41423-023-01079-w.)
(Cell Mol Immunol. 2023 Aug 31. doi: 10.1038/s41423-023-01079-w.)
B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3
Guojun Qian, Wenxia Jiang, Donglin Sun, Zhun Sun, Anning Chen, Hongwei Fang, Jingyao Wang, Yongzhong Liu, Zhinan Yin, Haiming Wei, Hao Fang, Xiaoren Zhang
Abstract
Aeroallergen sensitization, mainly mediated by lung epithelium and dendritic cells (DCs), is integral to allergic asthma pathogenesis and progression. IL-10 has a dual role in immune responses, as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation. Here, we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma. Specifically, Bcl-3 mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites (HDMs). IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells. Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development. IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3-Blimp-1-Bcl-6 regulation. Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization, thereby demonstrating resistance to HDM-induced asthma. Moreover, responses to HDM stimulation in Bcl-3 mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3 mice. The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production. Thus, targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma. IL-10 is released rapidly from lung plasma cells under Bcl-3-Blimp-1-Bcl-6 regulation upon house dust mite exposure and amplifies lung epithelial cell (EC)-derived CCL-20 production and subsequent dendritic cell (DC) recruitment to promote allergic sensitization in asthma. -/--/-+/+
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DOCK2通过引发气道上皮-间质转化来促进哮喘的发展
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