Gas6/Axl signaling attenuates alveolar inflammation in ischemia-reperfusion-induced acute lung injury by up-regulating SOCS3-mediated pathway

Abstract

Background Axl is a cell surface receptor tyrosine kinase, and activation of the Axl attenuates inflammation induced by various stimuli. Growth arrest-specific 6 (Gas6) has high affinity for Axl receptor. The role of Gas6/Axl signaling in ischemia-reperfusion-induced acute lung injury (IR-ALI) has not been explored previously. We hypothesized that Gas6/Axl signaling regulates IR-induced alveolar inflammation via a pathway mediated by suppressor of cytokine signaling 3 (SOCS3). Methods IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted to a control group and IR groups, which were treated with three different doses of Gas6. Mouse alveolar epithelium MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without Gas6 and Axl inhibitor R428 pretreatment. Results We found that Gas6 attenuated IR-induced lung edema, the production of proinflammatory cytokines in perfusates, and the severity of ALI ex vivo. IR down-regulated SOCS3 expression and up-regulated NF-κB, and Gas6 restored this process. In the model of MLE-12 cells with HR, Gas6 suppressed the activation of TRAF6 and NF-κB by up-regulating SOCS3. Axl expression of alveolar epithelium was suppressed in IR-ALI but Gas6 restored phosphorylation of Axl. The anti-inflammatory effect of Gas6 was antagonized by R428, which highlighted that phosphorylation of Axl mediated the protective role of Gas6 in IR-ALI. Conclusions Gas6 up-regulates phosphorylation of Axl on alveolar epithelium in IR-ALI. The Gas6/Axl signaling activates the SOCS3-mediated pathway and attenuates IR-related inflammation and injury.

Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2

“…TAM RTKs have been shown to reduce JAK/STAT-mediated immune responses 21 , 48 , while TAM triple knock-out activates the production of inflammatory cytokines 49 . Blockage of Axl in our disease settings induced pro-inflammatory signaling, consistent with a recent study in which R428 antagonized the anti-inflammatory effect of Gas6 in ischemia reperfusion-induced acute lung injury, suggesting that Gas6-induced Axl phosphorylation is protective not only in alveolar epithelium 50 , but also in the vascular endothelium.…”

Gas6 Ameliorates Inflammatory Response and Apoptosis in Bleomycin-Induced Acute Lung Injury

“…We administered BLM (5 U/kg in 30 μL) by mouse pharyngeal aspiration [ 37 , 38 ]. rGas6 (50 μg/kg) or saline treatment (BLM + Sal) was given intraperitoneally 1 h before BLM treatment, and then once a day thereafter [ 30 , 31 ]. Mice were euthanized on day 1, 2, or 7 following BLM treatment.…”

“…Previous research suggests that Gas6 signaling has a protective role in mice models of multi-organ dysfunction syndrome, ALI in sepsis, and ischemia/reperfusion-induced ALI [ 28 , 29 , 30 , 31 ]. In contrast, Gas6 or Mer deficiency is protective against silica-induced lung inflammation and fibrosis in mice [ 32 ].…”

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

“…A consequence of these anti-inflammatory functions of the GAS6-PROS1/TAM system is its effect on models of acute inflammation. In particular, GAS6 has been shown to attenuate the ischemia reperfusion damage in liver [ 29 ], kidney [ 30 ], and lung [ 31 ]. Not surprisingly, the administration of recombinant GAS6 diminishes deleterious effects of sepsis, including acute lung injury [ 32 ] and the endothelial hyper-permeability that is associated with bacterial endotoxemia [ 33 ].…”