靶向P2Y13受体抑制IL-33和HMGB1的释放并改善实验性哮喘
2021/12/24
摘要
理由：警报素IL-33和HMGB1（高迁移率族蛋白1）参与2型炎症和哮喘发病机制。
目的：确定嘌呤能G蛋白偶联受体（GPCR）和哮喘风险等位基因P2Y13受体（P2Y13-R）是否调节IL-33和HMGB1的释放。
方法：对健康和哮喘患者行支气管活检。原代人气道上皮细胞（AECs）、原代小鼠（m）AECs或C57Bl/6小鼠接种各种空气过敏原或呼吸道病毒，并通过免疫组织化学和ELISA测定警报素的核-细胞质易位和释放。使用药物拮抗剂和P2Y13-R基因缺失小鼠评估P2Y13-R在AEC功能以及在哮喘模型发病、进展和恶化中的作用。
测量和主要结果：空气过敏原暴露诱导ADP和ATP的细胞外释放，激活P2Y13-R的核苷酸。ATP、ADP、空气过敏原（屋尘螨、蟑螂或交链孢）或病毒暴露诱导核-细胞质易位，随后释放IL-33和HMGB1，这种反应被P2Y13的基因缺失或药理拮抗作用所消除。在小鼠中，预防性或治疗性P2Y13-R阻断可减轻哮喘发作，并消除慢性哮喘实验模型中鼻病毒相关的恶化。此外，P2Y13-R拮抗作用降低了抗病毒免疫，增加了IFN-λ的产生，减少了肺部的病毒拷贝数。
结论：我们确定P2Y13-R是核警报蛋白IL-33和HMGB1的新型守门人，并证明通过基因缺失或小分子拮抗剂治疗靶向此GPCR可防止实验性哮喘的发作和恶化。
Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma
Rhiannon B Werder, Md Ashik Ullah, Muhammed Mahfuzur Rahman, Jennifer Simpson, Jason P Lynch, Natasha Collinson, Sonja Rittchen, Ridwan B Rashid, Md Al Amin Sikder, Herlina Y Handoko, Bodie F Curren, Ismail Sebina, Gunter Hartel, Alec Bissell, Sylvia Ngo, Tejasri Yarlagadda, Sumaira Z Hasnain, Wenying Lu, Sukhwinder S Sohal, Megan Martin, Simon Bowler, Lucy D Burr, Laurent O Martinez, Bernard Robaye, Kirsten Spann, Manuel A R Ferreira, Simon Phipps
Abstract
Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type-2 inflammation and asthma pathogenesis.
Objectives: To determine whether P2Y13 receptor (P2Y13-R), a purinergic G protein-coupled receptor (GPCR) and risk allele for asthma, regulates the release of IL-33 and HMGB1.
Methods: Bronchial biopsies were obtained from healthy and asthmatic subjects. Primary human airway epithelial cells (AECs), primary mouse (m)AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins measured by immunohistochemistry and ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and an exacerbation of experimental asthma, was assessed using pharmacological antagonists and P2Y13-R gene-deleted mice.
Measurements and main results: Aeroallergen-exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, aeroallergen (house dust mite, cockroach or Alternaria) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset, and critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung.
Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1, and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.
理由：警报素IL-33和HMGB1（高迁移率族蛋白1）参与2型炎症和哮喘发病机制。
目的：确定嘌呤能G蛋白偶联受体（GPCR）和哮喘风险等位基因P2Y13受体（P2Y13-R）是否调节IL-33和HMGB1的释放。
方法：对健康和哮喘患者行支气管活检。原代人气道上皮细胞（AECs）、原代小鼠（m）AECs或C57Bl/6小鼠接种各种空气过敏原或呼吸道病毒，并通过免疫组织化学和ELISA测定警报素的核-细胞质易位和释放。使用药物拮抗剂和P2Y13-R基因缺失小鼠评估P2Y13-R在AEC功能以及在哮喘模型发病、进展和恶化中的作用。
测量和主要结果：空气过敏原暴露诱导ADP和ATP的细胞外释放，激活P2Y13-R的核苷酸。ATP、ADP、空气过敏原（屋尘螨、蟑螂或交链孢）或病毒暴露诱导核-细胞质易位，随后释放IL-33和HMGB1，这种反应被P2Y13的基因缺失或药理拮抗作用所消除。在小鼠中，预防性或治疗性P2Y13-R阻断可减轻哮喘发作，并消除慢性哮喘实验模型中鼻病毒相关的恶化。此外，P2Y13-R拮抗作用降低了抗病毒免疫，增加了IFN-λ的产生，减少了肺部的病毒拷贝数。
结论：我们确定P2Y13-R是核警报蛋白IL-33和HMGB1的新型守门人，并证明通过基因缺失或小分子拮抗剂治疗靶向此GPCR可防止实验性哮喘的发作和恶化。
(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)
(Am J Respir Crit Care Med. 2021 Dec 3. doi: 10.1164/rccm.202009-3686OC.)
(Am J Respir Crit Care Med. 2021 Dec 3. doi: 10.1164/rccm.202009-3686OC.)
Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma
Rhiannon B Werder, Md Ashik Ullah, Muhammed Mahfuzur Rahman, Jennifer Simpson, Jason P Lynch, Natasha Collinson, Sonja Rittchen, Ridwan B Rashid, Md Al Amin Sikder, Herlina Y Handoko, Bodie F Curren, Ismail Sebina, Gunter Hartel, Alec Bissell, Sylvia Ngo, Tejasri Yarlagadda, Sumaira Z Hasnain, Wenying Lu, Sukhwinder S Sohal, Megan Martin, Simon Bowler, Lucy D Burr, Laurent O Martinez, Bernard Robaye, Kirsten Spann, Manuel A R Ferreira, Simon Phipps
Abstract
Rationale: The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type-2 inflammation and asthma pathogenesis.
Objectives: To determine whether P2Y13 receptor (P2Y13-R), a purinergic G protein-coupled receptor (GPCR) and risk allele for asthma, regulates the release of IL-33 and HMGB1.
Methods: Bronchial biopsies were obtained from healthy and asthmatic subjects. Primary human airway epithelial cells (AECs), primary mouse (m)AECs, or C57Bl/6 mice were inoculated with various aeroallergens or respiratory viruses, and the nuclear-to-cytoplasmic translocation and release of alarmins measured by immunohistochemistry and ELISA. The role of P2Y13-R in AEC function and in the onset, progression, and an exacerbation of experimental asthma, was assessed using pharmacological antagonists and P2Y13-R gene-deleted mice.
Measurements and main results: Aeroallergen-exposure induced the extracellular release of ADP and ATP, nucleotides that activate P2Y13-R. ATP, ADP, aeroallergen (house dust mite, cockroach or Alternaria) or virus exposure induced the nuclear-to-cytoplasmic translocation and subsequent release of IL-33 and HMGB1, and this response was ablated by genetic deletion or pharmacological antagonism of P2Y13. In mice, prophylactic or therapeutic P2Y13-R blockade attenuated asthma onset, and critically, ablated the severity of a rhinovirus-associated exacerbation in a high-fidelity experimental model of chronic asthma. Moreover, P2Y13-R antagonism derepressed antiviral immunity, increasing IFN-λ production and decreasing viral copies in the lung.
Conclusions: We identify P2Y13-R as a novel gatekeeper of the nuclear alarmins IL-33 and HMGB1, and demonstrate that the targeting of this GPCR via genetic deletion or treatment with a small-molecule antagonist protects against the onset and exacerbations of experimental asthma.
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