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RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury.

ABSTRACT: Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperoxidase (MPO) and reducing its levels and activity. Moreover, RNF128 regulates alveolar macrophage activation and neutrophil infiltration by interacting with TLR4, targeting it for degradation, and inhibiting NF-κB activation, hence decreasing pro-inflammatory cytokines. Our results demonstrate for the first time that RNF128 is a negative regulator of MPO and TLR4 in neutrophils and alveolar macrophages, respectively. However, AAV9-mediated RNF128 overexpression alleviated lung tissue damage and reduced inflammatory cell infiltration. Thus, RNF128 is a promising therapeutic candidate for pharmacological interventions in ALI.

SUBMITTER: Liu PY

PROVIDER: S-EPMC10284794 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury.

Liu Pei-Yao PY Chen Chih-Yuan CY Lin Yu-Lung YL Lin Chien-Ming CM Tsai Wen-Chiuan WC Tsai Yu-Ling YL Lin Gu-Jiun GJ Chen Yu-Guang YG Wang Shih-Yun SY Sun Rui-Nong RN Huang Yu-Chuan YC Chang Hung H Chen Ying-Chuan YC

Cell death & disease 20230621 6

Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperox ...[more]

PMID: 37344492

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Project description:BACKGROUND:Hypercoagulation and neutrophilia are described in several cancers, however, whether they are involved in lung carcinogenesis is currently unknown. Emodin is the main bioactive component from Rheum palmatum and has many medicinal values, such as anti-inflammation and anticancer. This study is to investigate the contributions of neutrophils to the effects of emodin on hypercoagulation and carcinogenesis. METHODS:The effects of emodin on neutrophil phenotypes were assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The anti-coagulation and cancer-preventing actions of emodin were evaluated in the urethane-induced lung carcinogenic model. The expressions of Cit-H3 and PAD4 in lung sections were assessed by immunohistochemistry, CD66b+ neutrophils were distinguished by immunofluorescence, and cytokines and ROS were examined with ELISA. The neutrophils-regulating and hypercoagulation-improving efficacies of emodin were confirmed in a Lewis lung cancer allograft model. The related targets and pathways of emodin were predicted by network pharmacology. RESULTS:In vitro, emodin at the dose of 20 µM had no effect on cell viability in HL-60N1 but increased ROS and decreased autophagy and thus induced apoptosis in HL-60N2 with the morphological changes. In the urethane-induced lung carcinogenic model, before lung carcinogenesis, urethane induced obvious hypercoagulation which was positively correlated with lung N2 neutrophils. There were the aggravated hypercoagulation and lung N2 neutrophils after lung carcinoma lesions. Emodin treatment resulted in the ameliorated hypercoagulation and lung carcinogenesis accompanied by the decreased N2 neutrophils (CD66b+) in the alveolar cavity. ELISA showed that there were more IFN-γ, IL-12 and ROS and less IL-6, TNF-α and TGF-β1 in the alveolar cavity in the emodin group than those in the control group. Immunohistochemical analysis showed that emodin treatment decreased Cit-H3 and PAD4 in lung sections. In the Lewis lung cancer allograft model, emodin inhibits tumor growth accompanied by the attenuated coagulation and intratumor N2 neutrophils. Network pharmacology indicated the multi-target roles of emodin in N2 neutrophil activation. CONCLUSIONS:This study suggests a novel function of emodin, whereby it selectively suppresses N2 neutrophils to prevent hypercoagulation and lung carcinogenesis.

Project description:BackgroundVentilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury.MethodsWe administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε.ResultsNicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice.ConclusionsNicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but paradoxically also leads to the development of significant hypoxemia. These findings suggest that pulmonary neutrophilia is not linked to hypoxemia in ventilator-induced lung injury, and that nicotinamide exacerbates hypoxemia during VILI.

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RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury.

Publications

RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury.

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