JAK2/STAT1-mediated HMGB1 translocation increases inflammation and cell death in a ventilator-induced lung injury model

Abstract

Janus kinase 2/signal transducer and activators of transcription 1 (JAK2/STAT1) signaling is a common pathway that contributes to numerous inflammatory disorders, including different forms of acute lung injury (ALI). However, the role of JAK2/STAT1 in ventilator-induced lung injury (VILI) and its underlying mechanism remain unclear. In this study, using lipopolysaccharide (LPS) inhalation plus mechanical ventilation as VILI mouse model, we found that the administration of JAK2 inhibitor AZD1480 markedly attenuated lung destruction, diminished protein leakage, and inhibited cytokine release. In addition, when mouse macrophage-like RAW 264.7 cells were exposed to LPS and cyclic stretch (CS), AZD1480 prevented cell autophagy, reduced apoptosis, and suppressed lactate dehydrogenase release by downregulating JAK2/STAT1 phosphorylation levels and inducing HMGB1 translocation from the nucleus to the cytoplasm. Furthermore, HMGB1 and STAT1 knockdown attenuated LPS+CS-induced autophagy and apoptosis in RAW 264.7 cells. In conclusion, these findings reveal the connection between the JAK2/STAT1 pathway and HMGB1 translocation in mediating lung inflammation and cell death in VILI, suggesting that these molecules may serve as novel therapeutic targets for VILI.

CCL7 contributes to angiotensin II‐induced abdominal aortic aneurysm by promoting macrophage infiltration and pro‐inflammatory phenotype

“…It is widely known that STAT1 is crucial for M1 polarization while STAT6 is involved in M2 polarization 9 . Activation of JAK2/STAT1 pathway has been demonstrated to contribute to various inflammatory diseases through leading macrophage towards M1 phenotype 9,48‐51 . In our ex vivo experiment, we defined CCL7 as a critical regulator of JAK2/STAT1 pathway in macrophages.…”

“…9 Activation of JAK2/STAT1 pathway has been demonstrated to contribute to various inflammatory diseases through leading macrophage towards M1 phenotype. 9,[48][49][50][51] In our ex vivo experiment, we defined CCL7 as a critical regulator of JAK2/STAT1 pathway in macrophages. Furthermore, CCL7 triggered M1 polarization was relied on JAK2/STAT1 activation.…”

Long noncoding RNA SNHG4 remits lipopolysaccharide-engendered inflammatory lung damage by inhibiting METTL3 – Mediated m6A level of STAT2 mRNA

“…STAT may contribute to the development of acute lung injury in ammation. A research revealed that Azd1480, STAT2 inhibitor, could signi cantly reduce lung injury, reduce protein leakage and inhibit in ammatory cytokines release [20]. Cooperative networks of posttranscriptional modi cation pathways may ultimately regulate cell fate determination or stress by coordinating mRNA stability, translation e ciency, and splicing of transcripts that maintain cell type speci c proteomes.…”

MiR‐382‐5p suppresses M1 macrophage polarization and inflammatory response in response to bronchopulmonary dysplasia through targeting CDK8: Involving inhibition of STAT1 pathway

“…STAT1 is known as a pivotal transcription factor in the regulation of immune responses, which is required for governing macrophage activation (Liu et al., 2019). A recent study uncovered that STAT1 activation, mainly induced by IFN‐γ, can polarize macrophages to the M1 Phenotype (Sica & Mantovani, 2012).…”