Xin Liu,Wu Luo,Jiahao Chen,Chenghong Hu,Rumbidzai N. Mutsinze,Xu Wang,Yanmei Zhang,Lijiang Huang,Wei Zuo,Guang Liang,Yi Wang
Background & Aims Severe acute pancreatitis can easily lead to systemic inflammatory response syndrome and death. Macrophages are known to be involved in the pathophysiology of acute pancreatitis (AP), and macrophage activation correlates with disease severity. In this study, we examined the role of ubiquitin-specific protease 25, a deubiquitinating enzyme and known regulator of macrophages, in the pathogenesis of AP. Methods We used L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP in Usp25 -/- mice and wild-type mice. We also generated bone marrow Usp25 -/- chimeric mice and initiated L-arginine–mediated AP. Primary acinar cells and bone marrow–derived macrophages were isolated from wild-type and Usp25 -/- mice to dissect molecular mechanisms. Results Our results show that Usp25 deficiency exacerbates pancreatic and lung injury, neutrophil and macrophage infiltration, and systemic inflammatory responses in L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP. Bone marrow Usp25 -/- chimeric mice challenged with L-arginine show that Usp25 deficiency in macrophages exaggerates AP by up-regulating the TANK-binding kinase 1 (TBK1)–nuclear factor-κB (NF-κB) signaling pathway. Similarly, in vitro data confirm that Usp25 deficiency enhances the TBK1–NF-κB pathway, leading to increased expression of inflammatory cytokines in bone marrow–derived macrophages. Conclusions Usp25 deficiency in macrophages enhances TBK1–NF-κB signaling, and the induction of inflammatory chemokines and type I interferon-related genes exacerbates pancreatic and lung injury in AP.
Ethnopharmacological relevance Pulmonary fibrosis (PF) is an irreversible lung disease that severely affects human respiratory function. Traditionally, the natural plant Quzhou Fructus Arantii (QFA) has therapeutic effects on respiratory diseases. However, the effects and the mechanism of anti-fibrotic have not been elucidated. Aim of the study In this study, QFAE-nB was extracted from QFA, the aims of this study include understanding the correlation between Bleomycin (BLM)-induced PF and STING pathway in mice, as well as exploring the role and mechanisms of QFAE-nB in the treatment of PF. Materials and methods QFAE-nB was extracted from QFA, six main chemical components in QFAE-nB were identified by HPLC–QTOF–MS/MS, and quantitative analysis was conducted by HPLC. qPCR and Western blot were used to verify the molecular mechanism of QFAE-nB, and the anti-fibrotic effect of QFAE-nB was determined by hematoxylin-eosin (HE) staining and Masson staining as well as immunohistochemistry. TREX1-KO and STING-KO mice were used to verify the relationship between STING and PF and the important target action of QFAE-nB. Results Six main flavonoids in QFAE-nB were identified as eriocitrin (0.76%), neoeriocitrin (2.79%), narirutin (4.31%), naringin (35.41%), hesperidin (1.74%), and neohesperidin (27.18%). The results showed that BLM-induced PF was associated with its exacerbated release of proinflammatory factors and chemokines in lung tissues. In addition, QFAE-nB alleviated BLM-induced lung fibrosis in mice by inhibiting the activation of the STING signaling pathway and reducing the signal transduction of TBK1–IRF3 and TBK1–NF-κB pathways. Notably, knockout of the TREX1 gene caused massive inflammation and even induced PF in the lung tissues, whereas QFAE-nB effectively alleviated inflammation and reduced PF. The deletion of the STING gene suppressed BLM-induced PF and inflammation, but STING-KO mice treated with QFAE-nB showed even lower expression levels of proinflammatory factors and chemokine. Conclusions The STING pathway plays an important role in PF, and QFAE-nB alleviates PF by mainly targeting the inhibition of the STING pathway to reduce inflammation. Together, the study paves the way for targeting the STING pathway in PF treatment.
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