{"doi":"10.1016/j.redox.2024.103455","title":"Macrophage Dvl2 deficiency promotes NOD1-Driven pyroptosis and exacerbates inflammatory liver injury","abstract":"Dishevelled 2 (Dvl2) is a key mediator of the Wingless/Wnt signaling pathway that regulates cell proliferation, migration, and immune function. However, little is known about the role of macrophage Dvl2 in modulating NOD1-mediated pyroptosis and hepatocyte death in oxidative stress-induced inflammatory liver injury. In a mouse model of oxidative stress -induced liver inflammation , mice with myeloid-specific Dvl2 knockout (Dvl2 M-KO ) displayed exacerbated ischemia/reperfusion (IR) stress-induced hepatocellular damage with increased serum ALT levels, oxidative stress, and proinflammatory mediators. Unlike in Dvl2 FL/FL controls, Dvl2 M-KO enhanced NOD1, caspase-1, GSDMD, and NF-κB activation in liver macrophages after IR. Interestingly, IR stress enhanced YAP colocalized with HSF1 in Dvl2 FL/FL macrophages, while macrophage Dvl2 deficiency reduced YAP and HSF1 colocalization in the nucleus under inflammatory conditions. Importantly, Dvl2 deletion diminished nuclear YAP interacted with HSF1 and augmented NOD1/caspase-1 and GSDMD activation in response to inflammatory stimulation. However, Dvl2 activation increased YAP interaction with HSF1 and activated HSF1 target gene eEF2, inhibiting NOD1/caspase-1, GSDMD, and NF-κB activity. Moreover, macrophage eEF2 deletion increased the NOD1-caspase-1 interaction, GSDMD activation, HMGB1 release, and hepatocyte LDH release after macrophage/hepatocyte co-culture. Adoptive transfer of eEF2-expressing macrophages in Dvl2 M-KO mice alleviated IR-triggered liver inflammation and hepatocellular damage. Therefore, macrophage Dvl2 deficiency promotes NOD1-mediated pyroptosis and exacerbates IR-induced hepatocellular death by disrupting the YAP-HSF1 axis. eEF2 is crucial for modulating NOD1-driven pyroptosis, inflammatory response, and hepatocyte death. Our findings underscore a novel role of macrophage Dvl2 in modulating liver inflammatory injury and imply the therapeutic potential in organ IRI and transplant recipients. • Macrophage Dvl2 deficiency induces NOD1 and GSDMD activation, exacerbating IR stress-induced liver damage. • Disruption of macrophage Dvl2 inhibits the YAP and HSF1 signaling pathways in IR-stressed liver. • YAP functions as a transcriptional coactivator of HSF1 in regulating NOD1-mediated liver inflammation and pyroptotic cell death in IR-stressed liver. • Disruption of Dvl2 inhibits the YAP-HSF1 interaction and enhances NOD1 function in macrophages. • The YAP-HSF1 axis targets eEF2, crucial to regulate NOD1-mediated macrophage pyroptosis and Calcineurin/TRPM7-induced hepatocyte death in response to oxidative stress.","journal":"Redox Biology","year":2024,"id":441578,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9437,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":289494,"name":"Dongwei Xu","orcid":"0000-0001-9802-0664","position":1,"is_corresponding":false},{"id":824959,"name":"Tao Yang","orcid":"0000-0002-1127-9364","position":2,"is_corresponding":false},{"id":289495,"name":"Yizhu Tian","orcid":"0000-0002-0782-1704","position":3,"is_corresponding":false},{"id":1255098,"name":"Christopher T. King","orcid":null,"position":4,"is_corresponding":false},{"id":1060761,"name":"Xiao Wang","orcid":"0000-0002-9647-8847","position":5,"is_corresponding":false},{"id":289492,"name":"Mingwei Sheng","orcid":"0000-0001-6847-6345","position":6,"is_corresponding":false},{"id":289493,"name":"Yuanbang Lin","orcid":"0000-0003-0123-1241","position":7,"is_corresponding":false},{"id":1216988,"name":"Xiyun Bian","orcid":"0000-0002-5147-1297","position":8,"is_corresponding":false},{"id":289491,"name":"Changyong Li","orcid":"0000-0003-4001-037X","position":9,"is_corresponding":false},{"id":289496,"name":"Longfeng Jiang","orcid":"0000-0001-8058-6838","position":10,"is_corresponding":false},{"id":643940,"name":"Qiang Xia","orcid":"0000-0001-9482-6951","position":11,"is_corresponding":false},{"id":253609,"name":"Douglas G. 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