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Hepatokine ORM2 suppresses pathological ferritinophagy to prevent acute tissue injury

ABSTRACT: Acute tissue injuries trigger rapid cellular damage, but cell-intrinsic protective programs attenuate pathology through regulatory axes. Here, we demonstrate that Orosomucoid 2 (ORM2), a hepatokine, is significantly upregulated during drug-induced acute liver injury. Knock out Orm2 exacerbates liver damage, while its overexpression provides protection, identifying ORM2 as an endogenous hepatoprotective factor during acute liver injury. Mechanistically, ORM2 disrupts the FTH-NCOA4-TAX1BP1 interaction, thereby blocking ferritinophagy and preventing iron overload-induced cytotoxicity. Furthermore, acute ischemia-reperfusion injuries in other organs also trigger hepatic ORM2 upregulation and secretion, demonstrating liver-organ crosstalk via the circulatory system. Exogenous administration of ORM2 effectively ameliorates ferroptosis and tissue damage in multiple ischemia-reperfusion injury models. Collectively, our results identify the hepatokine ORM2 as a key suppressor of pathological ferritinophagy. This function positions ORM2 protein as a potential therapeutic candidate for acute tissue injuries driven by ferritinophagy-mediated iron overload.

ORGANISM(S): Mus musculus

PROVIDER: GSE277619 | GEO | 2024/09/22

REPOSITORIES: GEO

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Project description:Upon liver injury, altered cholangiocyte functions can lead to a process referred to as ductular reaction (DR), which is an umbrella term harboring not excessive cell proliferation, but also intricate inflammation and fibrogenesis modulation. DR has been considered as an essential hallmark and promising therapeutic target in a variety of liver diseases. However, the potentially broad implications of DR are rarely known due to the lack of effective investigational models. In this study, transcriptomic exploration methods were utilized to determine key factors resulting from injured cholangiocytes and in macrophage alterations, while multiplex immunofluorescent detection together with an in-house optimized image processing approaches were utilized to explore spatial counterparts in situ. Furthermore, co-culture systems (microchambers and liver-on-a-chip) equipped with multiple mouse strain-derived primary liver and circulating immune cells were employed to capitulate multi-cellular interactions upon biliary injury and to study mechanistic influencers. Results illustrated that Orosomucoid 2 (ORM2) was screened out as one of the most strongly induced secretory factors expressed by mouse-derived intrahepatic cholangiocytes under bile duct injury. Furthermore, ORM2-induced monocyte recruitment and potent transcriptome alterations in liver macrophages are associated with an increase of pro-inflammatory cytokine secretion and expression of cell stress-related genes. Furthermore, ORM2-activated macrophages not only exacerbated cell stress and Orm2 expression in both cholangiocytes and hepatocytes, but also promoted fibrogenesis in hepatic stellate cells. In addition, ORM2 regulated liver macrophage functions via an ITPR2-dependent calcium pathway. In conclusion, cholangiocyte-derived ORM2 induces liver macrophage reprogramming via an ITPR2-dependent calcium pathway in response to acute and chronic biliary injury, serving as a promoter of liver disease progression. This study reveals a novel mechanism for cholangiocyte-macrophage crosstalk upon liver injury, which may draw more attention to this cellular duet as a potential therapeutic target.

Project description:The liver has a remarkable capacity to regenerate and thus compensates for repeated injuries through toxic chemicals, drugs, alcohol, or malnutrition for decades. However, largely unknown is how and when alterations in the liver occur due to tolerable damaging insults. To that end, we induced repeated liver injuries over ten weeks in a mouse model injecting carbon tetrachloride (CCl4) twice a week. We lost 10% of the study animals within the first six weeks, which was accompanied by a steady deposition of extracellular matrix (ECM) regardless of metabolic activity of the liver. From week six onwards, all mice survived, and in these mice ECM deposition was rather reduced suggesting ECM remodelling as a liver response contributing to better coping with repeated injuries. The data of time-resolved paired transcriptome and proteome profiling of 18 mice was subjected to multi-level network inference, using Knowledge guided Multi-Omics Network inference (KiMONo), identified multi-level key markers exclusively associated with the injury-tolerant liver response. Interestingly, pathways of cancer and inflammation were lighting up and were validated using independent data sets compiled of 1034 samples from publicly available human cohorts. Interestingly, a yet undescribed link to lipid metabolism in this damage-tolerant phase was identified. Immunostaining revealed an unexpected accumulation of small lipid droplets (microvesicular steatosis) in parallel to a recovery of catabolic processes of the liver to pre-injury levels. Further, mild inflammation was experimentally validated. Taken together, we identified week six as a critical time point to switch the liver response program from an acute response that fosters ECM accumulation to a tolerant “survival” phase with pronounced deposition of small lipid droplets in hepatocytes potentially protecting against the repetitive injury with toxic chemicals. Our data suggest that microsteatosis formation plus a mild inflammatory state represent biomarkers and probably functional liver requirements to resist chronic damage.

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Hepatokine ORM2 suppresses pathological ferritinophagy to prevent acute tissue injury

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