Otulin的下调可诱导中性粒细胞型哮喘中的炎性小体活化
2024/05/28
摘要
背景：中性粒细胞型哮喘(NA)是一种与类固醇抵抗和IL-1β过量产生相关的严重哮喘表型;然而，确切的机制尚不清楚。此外，TNF-α信号通路（IL-1β产生的调节因子）的功能障碍与自身免疫性卵巢肿瘤蛋白酶具有线性连锁特异性的去泛素化酶（otulin）的缺乏有关。
目的：我们假设巨噬细胞(Mφ)中的otulin下调可通过核苷酸结合域、富含亮氨酸的重复序列和pyrin结构域蛋白3 (NLRP3)炎症小体信号通路触发Mφ激活。
方法：我们评估了NA患者血液单核细胞亚群和NA小鼠肺泡Mφ中otulin的表达。此外，我们评估了otulin缺乏对骨髓来源的Mφ的功能后果影响。在体外和体内评估抑制受体相互作用蛋白激酶（RIPK）-1和 RIPK-3 对中性粒细胞和第3组先天淋巴样细胞（ILC3）的影响。
结果：当比较非经典单核细胞时，与健康对照组相比，NA患者的细胞内成分中观察到显著下调的otulin (P = 0.005)。此外，NA小鼠离体肺泡Mφ的表达比对照组小鼠低。在骨髓源性Mφ中敲低otulin后，我们观察到依赖于NLRP3炎性体的自发IL-1β产生。此外，通过阻断IL-1β在NA中的释放，RIPK-1和RIPK-3抑制剂联合处理可显著降低浸润的中性粒细胞和ILC3s。
结论：由上游触发因子otulin缺乏引起的IL-1β过量产生可能是NA的一个有希望的诊断和治疗靶点。
Downregulation of otulin induces inflammasome activation in neutrophilic asthma.
Quang Luu, Quoc, YeJi, Kim,
Abstrast
Background: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1β overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1β production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients.
Objective：We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway.
Methods: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo.
Results: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1β production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1β release in NA.
Conclusions: IL-1β overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.
背景：中性粒细胞型哮喘(NA)是一种与类固醇抵抗和IL-1β过量产生相关的严重哮喘表型;然而，确切的机制尚不清楚。此外，TNF-α信号通路（IL-1β产生的调节因子）的功能障碍与自身免疫性卵巢肿瘤蛋白酶具有线性连锁特异性的去泛素化酶（otulin）的缺乏有关。
目的：我们假设巨噬细胞(Mφ)中的otulin下调可通过核苷酸结合域、富含亮氨酸的重复序列和pyrin结构域蛋白3 (NLRP3)炎症小体信号通路触发Mφ激活。
方法：我们评估了NA患者血液单核细胞亚群和NA小鼠肺泡Mφ中otulin的表达。此外，我们评估了otulin缺乏对骨髓来源的Mφ的功能后果影响。在体外和体内评估抑制受体相互作用蛋白激酶（RIPK）-1和 RIPK-3 对中性粒细胞和第3组先天淋巴样细胞（ILC3）的影响。
结果：当比较非经典单核细胞时，与健康对照组相比，NA患者的细胞内成分中观察到显著下调的otulin (P = 0.005)。此外，NA小鼠离体肺泡Mφ的表达比对照组小鼠低。在骨髓源性Mφ中敲低otulin后，我们观察到依赖于NLRP3炎性体的自发IL-1β产生。此外，通过阻断IL-1β在NA中的释放，RIPK-1和RIPK-3抑制剂联合处理可显著降低浸润的中性粒细胞和ILC3s。
结论：由上游触发因子otulin缺乏引起的IL-1β过量产生可能是NA的一个有希望的诊断和治疗靶点。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(J Allergy Clin Immunol 2024 Apr 9;(0): doi: 10.1016/j.jaci.2024.03.021. IF: 10.228)
(J Allergy Clin Immunol 2024 Apr 9;(0): doi: 10.1016/j.jaci.2024.03.021. IF: 10.228)
Downregulation of otulin induces inflammasome activation in neutrophilic asthma.
Quang Luu, Quoc, YeJi, Kim,
Abstrast
Background: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1β overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1β production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients.
Objective：We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway.
Methods: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo.
Results: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1β production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1β release in NA.
Conclusions: IL-1β overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.
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哮喘易感基因Gasdermin B促进MAVS-TBK1信号传导和气道炎症
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通过多个数据集探索哮喘的分子机制
