The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury
The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury
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LPS 诱导的急性肺损伤中调节性 T 细胞通过 HMGB1/PTEN/β-Catenin 轴的调节
DOI：
10.3389/fimmu.2019.01612
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发表时间：
2019-07-25
影响因子：
7.3
通讯作者：
Chen, Xu-Lin
中科院分区：
文献类型：
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作者：
Zhou, Min;Feng, Haoshu;Chen, Xu-Lin
脓毒症所致的急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)仍是细菌感染致死的主要并发症。调节性T(Treg)细胞似乎是解决肺损伤的重要调节器。尽管进行了广泛的研究，巨噬细胞HMGB1/PTEN/β-catenin信号在ALI期间Treg发育中的作用知之甚少。目的：本研究旨在探讨HMGB1/PTEN/b-catenin信号通路在介导败血症小鼠肺损伤中CD4(+)CD25(+)Foxp3(+)Treg发育中的作用及其分子机制。(PTENM-KO/β-catenin(M-KO))小鼠用内毒素或重组HMGB1(RHMGB1)诱导ALI。通过体外共培养进一步分析HMGB1-PTEN轴的作用。方法和主要结果：在ALI小鼠模型中，阻断HMGB1或髓系特异性PTEN基因敲除(PTENM-KO)可增加动物的存活/体重，减少肺损伤，增加转化生长因子-β的产生，抑制ROR-γt和IL-17的表达，同时促进β-连环蛋白信号转导，增加内毒素或rHMGB诱导的肺损伤中CD4(+)CD25(+)Foxp3+Tregs的表达。值得注意的是，髓系特异性β-连环素消融术(b-cateninM-KO)导致动物存活率下降和肺损伤增加，并伴随着rHMGB诱导的ALI中CD4(+)CD25(+)Foxp3(+)Tregs的减少。此外，破坏巨噬细胞HMGB1/PTEN或激活β-catenin可显著增加体外培养的CD4(+)CD25(+)Foxp3(+)Treg。结论：HMGB1/PTEN/β-catenin信号通路是调节Treg发育的新途径，为脓毒症肺损伤提供了潜在的治疗靶点。
Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains the leading complication for mortality caused by bacterial infection. The regulatory T (Treg) cells appear to be an important modulator in resolving lung injury. Despite the extensive studies, little is known about the role of macrophage HMGB1/PTEN/beta-catenin signaling in Treg development during ALI.Objectives: This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/b-catenin signaling in mediating CD4(+)CD25(+)Foxp3(+) Treg development in sepsis-induced lung injury in mice.Setting: University laboratory research of First Affiliated Hospital of Anhui Medical University.Subjects: PTEN/beta-catenin Loxp and myeloid-specific knockout mice.Interventions: Groups of PTENloxp/beta-catenin(loxp) and myeloid-specific PTEN/b-catenin knockout (PTENM-KO/beta-catenin(M-KO)) mice were treated with LPS or recombinant HMGB1 (rHMGB1) to induce ALI. The effects of HMGB1-PTEN axis were further analyzed by in vitro co-cultures.Measures and Main Results: In a mouse model of ALI, blocking HMGB1 or myeloid-specific PTEN knockout (PTENM-KO) increased animal survival/body weight, reduced lung damage, increased TGF-beta production, inhibited the expression of ROR gamma t and IL-17, while promoting beta-catenin signaling and increasing CD4(+) CD25(+) Foxp3+ Tregs in LPS-or rHMGB-induced lung injury. Notably, myeloid-specific beta-catenin ablation (b-cateninM-KO) resulted in reduced animal survival and increased lung injury, accompanied by reduced CD4(+)CD25(+)Foxp3(+) Tregs in rHMGB-induced ALI. Furthermore, disruption of macrophage HMGB1/PTEN or activation of beta-catenin significantly increased CD4(+)CD25(+) Foxp3(+) Tregs in vitro.Conclusions: HMGB1/PTEN/beta-catenin signaling is a novel pathway that regulates Treg development and provides a potential therapeutic target in sepsis-induced lung injury.