A novel mechanism for the protection against acute lung injury by melatonin: mitochondrial quality control of lung epithelial cells is preserved through SIRT3-dependent deacetylation of SOD2.

The mitochondrial quality control of lung epithelial cells is disturbed during sepsis, which contributes to abnormal mitochondrial function and acute lung injury. Melatonin is one of the primary hormones secreted by the pineal gland, displaying favorable antioxidative actions in sepsis and cardiopulmonary disease. However, the potential roles and molecular basis of melatonin in lipopolysaccharide (LPS)-treated lung epithelial cells have not been explored and reported. Herein, we investigated whether melatonin could protect against sepsis-induced acute lung injury (ALI) and LPS-treated lung epithelial cells through the mitochondrial quality control as well as its possible molecular targets. Wild type and Sirt3 knockout mice were intratracheally instilled with LPS for 12 h to construct an in vivo acute lung injury model. Both A549 lung epithelial cells and primary alveolar type II (AT-II) cells were used to explore the possible roles of melatonin in vitro by incubating with small interfering RNA against Sirt3. To determine the involvement of the melatonin receptor, cells and mice were treated with si Mtnr1b and luzindole. Melatonin pretreatment significantly inhibited pathological injury, inflammatory response, oxidative stress, and apoptosis in LPS-treated lung tissues and LPS-treated lung epithelial cells. Furthermore, melatonin also shifted the dynamic course of mitochondria from fission to fusion, inhibited mitophagy and fatty acid oxidation in LPS-treated lung epithelial cells in vitro and in vivo. However, SIRT3 inhibition abolished the protective roles of melatonin in acute lung injury. Mechanistically, we found that melatonin increased the activity and expression of SIRT3, which further promoted the deacetylation of SOD2 at K122 and K68. More importantly, melatonin exerted pulmonary protection by activating MTNR1B but not MTNR1A during ALI. Collectively, melatonin could preserve the mitochondrial quality control of lung epithelial cells through the deacetylation of SOD2 in a SIRT3-dependent manner, which eventually alleviated sepsis-induced injury, inflammation, oxidative stress, and apoptosis. Thus, melatonin may serve as a promising candidate against ALI in the future.

The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury.

Histone deacetylase 3 (HDAC3) plays a crucial role in chromatin remodeling, which, in turn, regulates gene transcription. Hence, HDAC3 has been implicated in various diseases, including ischemic injury, fibrosis, neurodegeneration, infections, and inflammatory conditions. In addition, HDAC3 plays vital roles under physiological conditions by regulating circadian rhythms, metabolism, and development. In this review, we summarize the current knowledge of the physiological functions of HDAC3 and its role in organ injury. We also discuss the therapeutic value of HDAC3 in various diseases.

Cytosolic DNA-STING-NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide.

The role of NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis in acute lung injury (ALI) has been well identified previously. Stimulator of interferon genes (STING) is an indispensable adaptor protein, which could regulate inflammation and pyroptosis during infection; however, its role in lipopolysaccharide (LPS)-induced ALI remains obscure. This study aimed to explore whether STING participated in the development of LPS-induced ALI as well as the underlying mechanism. We confirmed that LPS significantly enhanced the expression and phosphorylation of STING in lung tissue and primary macrophages from mice. STING deficiency relieved inflammation and oxidative stress in LPS-treated murine lungs and macrophages. Meanwhile, STING deficiency also abolished the activation of NLRP3 inflammasome and pyroptosis; however, NLRP3 overexpression by adenovirus offset the beneficial effects of STING deficiency in macrophages treated with LPS. Additionally, the level of mitochondrial DNA (mt-DNA) significantly increased in macrophages after LPS treatment. Intriguingly, although exogenous mt-DNA stimulation did not influence the level of STING, it could still trigger the phosphorylation of STING as well as pyroptosis, inflammation, and oxidative stress of macrophages. And the adverse effects induced by mt-DNA could be offset after STING was knocked out. Furthermore, the inhibition of the sensory receptor of cytosolic DNA (cyclic GMP-AMP synthase, cGAS) also blocked the activation of STING and NLRP3 inflammasome, meanwhile, it alleviated ALI without affecting the expression of STING after LPS challenge. Furthermore, cGAS inhibition also blocked the production of cGAMP induced by LPS, indicating that mt-DNA and cGAS could activate STING-NLRP3-mediated pyroptosis independent of the expression of STING. Finally, we found that LPS upregulated the expression of transcription factor c-Myc, which subsequently enhanced the activity of STING promoter and promoted its expression without affecting its phosphorylation. Collectively, our study disclosed that LPS could activate STING in a cytosolic DNA-dependent manner and upregulate the expression of STING in a c-Myc-dependent manner, which cooperatively contribute to ALI.