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Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

ABSTRACT: Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.

SUBMITTER: Jin Z

PROVIDER: S-EPMC10730695 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

Jin Zhangchu Z Shao Zhehua Z Yang Shiyi S Guo Anyi A Han Yinling Y Wu Yinfang Y Zhao Yun Y Wu Yanping Y Shen Jiaxin J Zhang Min M Zhan Xueqin X Diao Wenqi W Ying Songmin S Zhang Chao C Li Wen W Shen Huahao H Chen Zhihua Z Yan Fugui F

Cell death & disease 20231219 12

Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deleti ...[more]

PMID: 38114479

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Project description:BackgroundAcute lung injury (ALI) is a severe condition characterized by inflammation, tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Angelica acutiloba Kitagawa, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI.MethodsALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays. NO release and mitochondrial membrane potential (MMP) were measured by JC-1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence.ResultsKAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both in vitro and in vivo analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA.ConclusionKAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.

Project description:BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.MethodsUsing Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining.ResultsWe reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1-/- mice, Ism1-/- lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages.ConclusionTogether with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.

Project description:Reactive oxidants such as nitrogen dioxide (NO(2)) injure the pulmonary epithelium, causing airway damage and inflammation. We previously demonstrated that nuclear factor-κ B (NF-κB) activation within airway epithelial cells occurs in response to NO(2) inhalation, and is critical for lipopolysaccharide-induced or antigen-induced inflammatory responses. Here, we investigated whether manipulation of NF-κB activity in lung epithelium affected severe lung injuries induced by NO(2) inhalation. Wild-type C57BL/6J, CC10-IκBα(SR) transgenic mice with repressed airway epithelial NF-κB function, or transgenic mice expressing a doxycycline-inducible, constitutively active I κ B kinase β (CC10-rTet-(CA)IKKβ) with augmented NF-κB function in airway epithelium, were exposed to toxic levels of 25 ppm or 50 ppm NO(2) for 6 hours a day for 1 or 3 days. In wild-type mice, NO(2) caused the activation of NF-κB in airway epithelium after 6 hours, and after 3 days resulted in severe acute lung injury, characterized by neutrophilia, peribronchiolar lesions, and increased protein, lactate dehydrogenase, and inflammatory cytokines. Compared with wild-type mice, neutrophilic inflammation and elastase activity, lung injury, and several proinflammatory cytokines were significantly suppressed in CC10-IκBα(SR) mice exposed to 25 or 50 ppm NO(2). Paradoxically, CC10-rTet-(CA)IKKβ mice that received doxycycline showed no further increase in NO(2)-induced lung injury compared with wild-type mice exposed to NO(2), instead displaying significant reductions in histologic parameters of lung injury, despite elevations in several proinflammatory cytokines. These intriguing findings demonstrate distinct functions of airway epithelial NF-κB activities in oxidant-induced severe acute lung injury, and suggest that although airway epithelial NF-κB activities modulate NO(2)-induced pulmonary inflammation, additional NF-κB-regulated functions confer partial protection from lung injury.

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Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

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Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

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