HMGB1-PTEN Axis Contributes To The Development Of Regulatory T Cells In Sepsis-induced Lung Injury

AT A GLANCE COMMENTARYScientific Knowledge on the SubjectSepsis, a syndrome mediated by systemic inflammatory response, may result in organ dysfunction/failure due to severe infection. Tregsare crucial in regulating inflammatory responses and mediating the resolution of lung injury. Despite the extensive study, the role of HMGB1‐PTEN axis in modulating Treg development during sepsis‐induced acute lung injury remains unknown.What This Study Adds to the FieldThis study demonstratesthat elevated circulating HMGB1 levels were accompanied by decreased Treg frequencies in patients with ALI/ARDS induced by sepsis, as compared with healthy subjects. In a murine model of ALI, blocking HMGB1 or myeloid PTEN deficiency promoted TGF‐β and β‐catenin/PDK1/Akt signaling pathways and increases the induction of CD4+CD25+Foxp3+Tregs in LPS‐ or r HMGB1‐treated mice. Using in vitro co‐culture system, we also demonstrate the regulatory role of macrophage HMGB1‐PTEN axis in Treg development during lung inflammatory response. These studies provide the rationale for novel therapeutic strategies to treat sepsis‐induced lung injury.AbstractRationale: Sepsis is a systemic inflammatory response syndrome which may result in acute lung injury(ALI) and/or acute respiratory distress syndrome(ARDS). Sepsis‐induced acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is aserious complication with a high mortality rate caused by bacterial infection. Despite recent progress in developing many pharmacological interventions, the clinical trials were unsuccessful, implying that the molecular mechanisms of sepsis‐driven inflammatory responses are complex and largely unknown. High‐mobility group box 1 protein(HMGB1) is a key mediator during inflammatory responses in sepsis.Recently, CD4+CD25+Foxp3+Tregs have been shown to be crucial for the resolution of endotoxin‐induced lung injury via both TGF‐β‐dependent and ‐independent pathways. The regulatory T(Treg) cells appears to be an important modulator in resolving lung injury. Deficiency of myeloid PTEN increases PI3 K signaling and reduces endotoxin‐induced inflammatory response and lung injury, whereas deletion of PDK1 in T cells results in reducing Treg numbers in vitro and in vivo. Thus, the modulation of Treg development might involve in multiple pathways during lung inflammation and injury.Despite the extensive study, little is known the role of HMGB1‐PTENaxis on macrophages may regulate the Treg development during sepsis‐induced lung injury.Objectives: This study was to determine the role and molecular mechanism of HMGB1‐PTEN axis in mediating CD4+CD25+Foxp3+Tregs in lung injury.Methods: Circulating levels of HMGB1 and CD4+CD25+CD127lowTregswere measured in sepsis‐induced ALI/ARDS patients and healthy subjects. The wild type and the myeloid‐specific PTEN knockout mice were subjected to LPS or recombinant HMGB1(r HMGB1) treatment to induceacute lung injury. The lung damage, the levels of HMGB1, TGF‐β, proinflammatory cytokines, and Tregswere determined. The expression of HMGB1, PTEN, β‐catenin, PDK1, and Akt was analyzed on macrophages and spleen Tcells.The effects of HMGB1‐PTEN axis were further analyzed by in vitro co‐cultures.Measures and Main Results: Significantly increased plasma levels of HMGB1 and reduced Tregs were present in sepsis‐induced ALI/ARDS patients compared to healthy subjects. Blocking HMGB1 or myeloid PTEN deficiency reduced lung damage, increased TGF‐β production, and promoted β‐catenin/PDK1/Akt signaling, which accompanied by increasing Treginduction in LPS‐ or r HMGB‐induced lung injury. Blockade of HMGB1‐PTEN axis resulted in significant augmentation of CD4+CD25+Foxp3+Tregsin vitro cultures.Conclusion: Using a well‐established model of lung injury and in vitro co‐culture system, we identifieda novel regulatory pathwayof HMGB1‐PTEN axis on Treg induction during inflammatory response. We demonstrate that HMGB1 promotes lung inflammation through activatingmyeloid PTEN‐mediated innate immunity. Lacking myeloid PTEN ultimately resulted in promoting TGF‐β and β‐catenin/PDK1/Akt signaling, which in turn induce CD4+CD25+Foxp3+Tregs and suppress endotoxin‐mediated inflammation in the lung. Our data document that disruption of HMGB1‐PTEN axisis critical for the development of Tregs in the resolution of sepsis‐induced lung injury.HMGB1‐PTEN axis is anovelpathwayto regulate Treg development and provides potential therapeutic target in sepsis‐induced lung injury.