下调otulin可诱导中性粒细胞性哮喘炎症小体活化
2024/04/24
摘要
背景：中性粒细胞性哮喘（NA）是一种重症哮喘表型，与激素抵抗和IL-1β过度生成相关，但具体机制尚不清楚。此外，肿瘤坏死因子-α（IL-1β生成的调节因子）信号通路的功能障碍与自身免疫患者中具有线性连锁特异性的OTU去泛素酶（otulin）的缺乏有关。
目的：本研究假设下调巨噬细胞（Mφ）中的otulin可以通过核苷酸结合结构域、富含亮氨酸的重复序列和含热蛋白（pyrin）结构域的蛋白3（NLRP3）炎症小体信号通路触发Mφ活化。
方法：本研究评估了otulin在NA患者外周血单核细胞亚群和NA小鼠肺泡Mφ中的表达情况。此外，本研究还评估了outlin缺乏对骨髓源性Mφ（BMDMs）功能的影响。通过体外和体内实验，本研究还评估了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组固有淋巴细胞（ILC3）的影响。
结果：与健康对照组相比，NA患者非经典单核细胞内的outlin显著下调（P=0.005）。此外，与对照组小鼠相比，NA组小鼠肺泡中分离的Mφ表达较低的otulin。敲低BMDMs中的otulin后，本研究观察到依赖于NLRP3炎症小体的IL-1β自发生成。此外，RIPK-1和RIPK-3抑制剂联合治疗可通过阻断NA中IL-1β释放，显著降低中性粒细胞和ILC3浸润。
结论：本研究结果表明，上游触发因子otulin缺乏可导致IL-1β过度生成，这有望成为NA的潜在诊断和治疗靶点。
Downregulation of otulin induces inflammasome activation in neutrophilic asthma.
Quoc QL, Kim Y, Park G, Tra Cao TB, Choi Y, Park YH, Park HS.
Abstract
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 tumor necrosis factor-alpha signaling pathway, a regulator of IL-1β production, was associated with the deficiency of OTU 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 (BMDMs). 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 non-classical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients when compared to healthy controls (P = 0.005). Additionally, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. Following otulin knockdown in BMDMs, 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.
CONCLUSION:Our findings suggest that 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：中性粒细胞性哮喘（NA）是一种重症哮喘表型，与激素抵抗和IL-1β过度生成相关，但具体机制尚不清楚。此外，肿瘤坏死因子-α（IL-1β生成的调节因子）信号通路的功能障碍与自身免疫患者中具有线性连锁特异性的OTU去泛素酶（otulin）的缺乏有关。
目的：本研究假设下调巨噬细胞（Mφ）中的otulin可以通过核苷酸结合结构域、富含亮氨酸的重复序列和含热蛋白（pyrin）结构域的蛋白3（NLRP3）炎症小体信号通路触发Mφ活化。
方法：本研究评估了otulin在NA患者外周血单核细胞亚群和NA小鼠肺泡Mφ中的表达情况。此外，本研究还评估了outlin缺乏对骨髓源性Mφ（BMDMs）功能的影响。通过体外和体内实验，本研究还评估了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组固有淋巴细胞（ILC3）的影响。
结果：与健康对照组相比，NA患者非经典单核细胞内的outlin显著下调（P=0.005）。此外，与对照组小鼠相比，NA组小鼠肺泡中分离的Mφ表达较低的otulin。敲低BMDMs中的otulin后，本研究观察到依赖于NLRP3炎症小体的IL-1β自发生成。此外，RIPK-1和RIPK-3抑制剂联合治疗可通过阻断NA中IL-1β释放，显著降低中性粒细胞和ILC3浸润。
结论：本研究结果表明，上游触发因子otulin缺乏可导致IL-1β过度生成，这有望成为NA的潜在诊断和治疗靶点。
(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)
(J Allergy Clin Immunol. 2024 Apr 8:S0091-6749(24)00337-3. doi: 10.1016/j.jaci.2024.03.021.)
(J Allergy Clin Immunol. 2024 Apr 8:S0091-6749(24)00337-3. doi: 10.1016/j.jaci.2024.03.021.)
Downregulation of otulin induces inflammasome activation in neutrophilic asthma.
Quoc QL, Kim Y, Park G, Tra Cao TB, Choi Y, Park YH, Park HS.
Abstract
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 tumor necrosis factor-alpha signaling pathway, a regulator of IL-1β production, was associated with the deficiency of OTU 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 (BMDMs). 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 non-classical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients when compared to healthy controls (P = 0.005). Additionally, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. Following otulin knockdown in BMDMs, 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.
CONCLUSION:Our findings suggest that 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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