CD39+ Regulatory T Cells Attenuate Lipopolysaccharide-Induced Acute Lung Injury via Autophagy and the ERK/FOS Pathway

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by an uncontrollable cytokine storm, which is associated with high mortality due to lack of effective treatment. Regulatory T cells (Tregs) play an indispensable role in maintaining immune homeostasis and CD39 is considered as a functional cell marker of Tregs. In this study, we aimed to evaluate the effect of CD39+ Tregs on acute lung injury (ALI) and investigate the frequency of CD39+ Tregs in ARDS patients. We found that after lipopolysaccharide (LPS) treatment, CD39−/− mice exhibited more severe inflammation and wild type (WT) mice exhibited a decreased frequency of CD39+ Tregs in the peripheral blood. Furthermore, CD39+ Tregs had a protective effect on LPS-induced inflammation in vitro and the adoptive transfer of CD39+ Tregs had a therapeutic effect on ALI in vivo. We further sought to explore the mechanisms that affect CD39 expression on Tregs. LPS-induced inflammation in the lung impaired the immunosuppressive effect of Tregs via the autophagy-mediated downregulation of CD39. In addition, CD39 induced the expression of itself in Tregs via activating the ERK1/2-FOS pathway. Consistent with this finding, the frequency of CD39+ Tregs was also decreased in the peripheral blood of ARDS patients and was positively correlated with disease severity. Our results suggested that the adoptive transfer of CD39+ Tregs may provide a novel method for the clinical prevention and treatment of ARDS.

Curcumin Elevates microRNA‐183‐5p via Cathepsin B‐Mediated Phosphatidylinositol 3‐Kinase/AKT Pathway to Strengthen Lipopolysaccharide‐Stimulated Immune Function of Sepsis Mice

“…As reported, Treg exerts a critical role in sustaining immune homeostasis, and CD39, an exonucleotide enzyme of hydrolytic proinflammatory ATP, is considered as a functional cell marker of Treg [20]. Antecedent studies have illuminated Tregs implicates in the pathogenesis of sepsis via stimulating immunosuppression [21].…”

Identification and Validation of Autophagy-Related Genes in Sepsis-Induced Acute Respiratory Distress Syndrome and Immune Infiltration

“… 25 Another study reported that CD39+ regulatory T cells attenuate LPS-induced ALI via autophagy and ERK/FOS pathway. 26 However, bioinformatics analysis of ARGs has not been well explored in sepsis-induced ARDS.…”

circEXOC5 promotes acute lung injury through the PTBP1/Skp2/Runx2 axis to activate autophagy

“…Some studies suggest elevated autophagy is a maladaptive response caused by incomplete autophagy activation, and therefore, completing or enhancing autophagy will alleviate ALI and improve the prognosis (Lo et al, 2013;Lin et al, 2014;Zhao et al, 2019;Nosaka et al, 2020;Peng et al, 2021;Zhang et al, 2021). On the contrary, other studies indicate activated autophagy is a pathogenic factor leading to ALI, and thus, inhibiting autophagy benefits the treatment (Sun et al, 2012;Hu et al, 2014;Zhu et al, 2017;Slavin et al, 2018;Chen et al, 2020;Li et al, 2020). In this study, we detected activated autophagy in CLPinduced ALI damages, as represented by the increased number of autophagosomes under TEM, the up-regulated expression and co-localization of LC3II and Beclin1, and the down-regulation of p62.…”