期刊
FRONTIERS IN IMMUNOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.01612
关键词
acute lung injury; HMGB1; regulatory T cells; sepsis; inflammation
类别
资金
- National Natural Science Foundation of China [81871584, 81201488, 81870060, 81671877, 81372050]
- Anhui Province Natural Science Foundation of China [KJ2017A199]
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.
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