AUTHOR=Zhou Min , Fang Haoshu , Du Min , Li Changyong , Tang Rui , Liu Haiyan , Gao Zhi , Ji Zongshu , Ke Bibo , Chen Xu-Lin
TITLE=The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury
JOURNAL=Frontiers in Immunology
VOLUME=10
YEAR=2019
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01612
DOI=10.3389/fimmu.2019.01612
ISSN=1664-3224
ABSTRACT=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/β-catenin signaling in Treg development during ALI.
Objectives: This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/β-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/β-catenin Loxp and myeloid-specific knockout mice.
Interventions: Groups of PTENloxp/β-cateninloxp and myeloid-specific PTEN/β-catenin knockout (PTENM−KO/β-cateninM−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-β production, inhibited the expression of RORγt and IL-17, while promoting β-catenin signaling and increasing CD4+CD25+Foxp3+ Tregs in LPS- or rHMGB-induced lung injury. Notably, myeloid-specific β-catenin ablation (β-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 β-catenin significantly increased CD4+CD25+Foxp3+ Tregs in vitro.
Conclusions: HMGB1/PTEN/β-catenin signaling is a novel pathway that regulates Treg development and provides a potential therapeutic target in sepsis-induced lung injury.