Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice
Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice
复制标题
促红细胞生成素通过 EPOR/JAK2/STAT3 途径抑制 NLRP3 炎症小体有助于减轻小鼠急性肺损伤
DOI：
10.3389/fphar.2020.00306
复制
发表时间：
2020-03-19
影响因子：
5.6
通讯作者：
Gao, Ye
中科院分区：
文献类型：
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作者：
Cao, Fei;Tian, Xinyi;Gao, Ye
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是常见的破坏性临床疾病，死亡率高且无特异性治疗。过度的炎症反应导致ALI/ARDS的进展，NLRP3炎症小体是炎症的关键参与者。临床上用于治疗贫血的促红细胞生成素（EPO），据报道在ALI中具有多效性。然而，EPO是否可以通过调节NLRP3炎性体来预防脂多糖（LPS）诱导的ALI及其潜在机制尚不清楚。本研究旨在探讨在lps诱导的ALI小鼠模型中，EPO的治疗作用是否依赖于抑制NLRP3炎性体及其具体机制。通过腹腔注射LPS （15 mg/kg）诱导C57BL/6小鼠ALI。LPS刺激后，以5u /g的剂量腹腔注射EPO。8 h后处死小鼠。我们的研究结果表明，EPO通过恢复组织病理学改变、降低肺干/湿（W/D）比、支气管肺泡灌洗液（BALF）蛋白浓度和髓过氧化物酶（MPO）水平，显著减轻lps诱导的肺损伤。同时，EPO显著降低白细胞介素-1β (IL-1β)和白细胞介素-18 （IL-18）的分泌，降低NLRP3炎性小体pro-IL-1β、NLRP3和cleaved caspase-1的表达，降低核因子-κB (NF-κB) p65的磷酸化，这可能与EPO受体（EPOR）的活化、janus -酪氨酸激酶2 （JAK2）和转录信号传导激活因子3 （STAT3）的磷酸化有关。然而，EPO对ALI和调节NLRP3炎性体的所有有益作用都被EPOR/JAK2/STAT3通路的抑制和NLRP3基因的敲除（KO）明显地抵消了。综上所述，本研究表明EPO可以通过抑制NLRP3炎性体有效减轻lps诱导的小鼠肺损伤，而NLRP3炎性体依赖于EPOR/JAK2/STAT3信号的激活和NF-κB通路的抑制。
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. An excessive inflammatory response results in the progression of ALI/ARDS, and the NLRP3 inflammasome is a key participant in inflammation. Erythropoietin (EPO), which is clinically used for anemia, reportedly exerts pleiotropic effects in ALI. However, whether EPO could protect against lipopolysaccharide (LPS)-induced ALI by regulating the NLRP3 inflammasome and its underlying mechanisms remain poorly elucidated. This study aimed to explore whether the therapeutic effects of EPO rely on the suppression of the NLRP3 inflammasome and the specific mechanisms in an LPS-induced ALI mouse model. ALI was induced in C57BL/6 mice by intraperitoneal (i.p.) injection of LPS (15 mg/kg). EPO was administered intraperitoneally at 5 U/g after LPS challenge. The mice were sacrificed 8 h later. Our findings indicated that application of EPO markedly diminished LPS-induced lung injury by restoring histopathological changes, lessened lung wet/dry (W/D) ratio, protein concentrations in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) levels. Meanwhile, EPO evidently decreased interleukin-1β (IL-1β) and interleukin-18 (IL-18) secretion, the expression of NLRP3 inflammasome components including pro-IL-1β, NLRP3, and cleaved caspase-1 as well as phosphorylation of nuclear factor-κB (NF-κB) p65, which may be associated with activation of EPO receptor (EPOR), phosphorylation of Janus-tyrosine kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). However, all the beneficial effects of EPO on ALI and modulation NLRP3 inflammasome were remarkably abrogated by the inhibition of EPOR/JAK2/STAT3 pathway and knockout (KO) of NLRP3 gene. Taken together, this study indicates that EPO can effectively attenuate LPS-induced lung injury in mice by suppressing the NLRP3 inflammasome, which is dependent upon activation of EPOR/JAK2/STAT3 signaling and inhibition of the NF-κB pathway.