Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice

Nguyen, Nga; Umbaugh, David S.; Smith, Sawyer; Adelusi, Olamide B.; Sánchez-Guerrero, Giselle; Ramachandran, Anup; Jaeschke, Hartmut

doi:10.1007/s00204-023-03478-4

Cited by 19 publications

(15 citation statements)

References 64 publications

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“…It is plausible that these proteins are indicative of a biological process that remains to be fully elucidated in APAP hepatotoxicity and contributes to poor outcomes in a subset of patients with APAP overdose. Interestingly, our recent work in mice delineated that after APAP overdose, there was greater neutrophil infiltration and a reduction in infiltrating macrophages, with neutrophils exacerbating injury, after a severe APAP overdose 41 . This lends some evidence that different immune programs can be initiated based on the APAP dose consumed, and that the difference in the immune response may influence the outcome in the patient with APAP overdose.…”

Section: Discussionmentioning

confidence: 91%

“…Interestingly, our recent work in mice delineated that after APAP overdose, there was greater neutrophil infiltration and a reduction in infiltrating macrophages, with neutrophils exacerbating injury, after a severe APAP overdose. [41] This lends some evidence that different immune programs can be initiated based on the APAP dose consumed, and that the difference in the immune response may influence the outcome in the patient with APAP overdose. Future work is needed to fully evaluate this possibility and determine its clinical relevance.…”

Section: Discussionmentioning

confidence: 95%

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The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

Umbaugh,

Nguyen,

Curry

et al. 2023

Hepatology

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Background and Aims: Patients with acetaminophen-induced acute liver failure (APAP-ALF) are more likely to die while on the liver transplant waiting list than those with other causes of ALF. Therefore, there is an urgent need for prognostic biomarkers that can predict the need for liver transplantation early after an APAP overdose. Approach and Results: We evaluated the prognostic potential of plasma chemokine CXCL14 concentrations in APAP overdose patients (n=50) and found CXCL14 is significantly higher in non-surviving patients compared to survivors with ALF (p<0.001). Logistic regression and AUROC analyses revealed that CXCL14 outperformed the MELD score better discriminating between non-survivors and survivors. We validated these data in a separate cohort of samples obtained from the Acute Liver Failure Study Group (n=80), where MELD and CXCL14 had similar AUC (0.778), but CXCL14 demonstrated higher specificity (81.2 vs. 52.6) and positive predictive value (82.4 vs. 65.4) for death or need for liver transplantation. Next, combining the patient cohorts and using a machine learning training/testing scheme to mimic the clinic scenario, we found that CXCL14 outperformed MELD based on AUC (0.821 vs. 0.787), however combining MELD and CXCL14 yielded the best AUC (0.860). Conclusions: We find in two independent cohorts of APAP overdose patients that circulating CXCL14 concentration is a novel early prognostic biomarker for poor outcome which may aid in guiding decisions regarding patient management. Moreover, our findings reveal that CXCL14 performs best when measured soon after patient presentation to the clinic, highlighting its importance for early warning of poor prognosis.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

Umbaugh,

Nguyen,

Curry

et al. 2023

Hepatology

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“…After APAP overdose, there is dose‐dependent damage, and the contribution of innate immune cells to APAP toxicity and inflammatory responses has been demonstrated to be dose‐dependent. [ 38 , 39 ] Among these, the mechanisms triggered following the administration of 600 mg kg −1 APAP are more closely associated with events that contribute to ALF in patients. However, for the exacerbated phenotype and extremely high mortality rate observed in the Mas1 −/− ‐APAP group, we finally chose to pursue further research using APAP at dosage of 300 mg kg −1 rather than 600 mg kg −1 , as previously described studies.…”

Section: Discussionmentioning

confidence: 99%

“…However, for the exacerbated phenotype and extremely high mortality rate observed in the Mas1 −/− ‐APAP group, we finally chose to pursue further research using APAP at dosage of 300 mg kg −1 rather than 600 mg kg −1 , as previously described studies. [ 40 , 41 , 42 , 43 ] Although specific inflammatory and repair responses are observed with high‐dose APAP exposure, [ 38 , 39 ] the phenotypic exacerbation resulting from Mas1 knockout can induce these reactions, even at lower dosage levels. This hypothesis was confirmed through our analysis of liver failure samples associated with DILI in humans who were also recipients of transplanted liver.…”

Section: Discussionmentioning

confidence: 99%

Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC⁺CD63⁺ Endothelial Cells, MMP12⁺ Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury

Chen,

Lu,

Zhao

et al. 2024

Advanced Science

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Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen‐induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein‐coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single‐cell RNA sequencing, spatial transcriptomics, and hour‐long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell‐specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF‐κB/TNF‐α signaling pathway due to myeloid‐Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets.

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“…They were also shown to induce tissue damage and impairment in numerous acute and chronic injury conditions ( 42 – 44 ). It is important to note that while acute liver injury induced by different doses of APAP promoted the influx of neutrophils into the liver, the contribution of these cells to the injury was revealed at higher APAP doses ( 178 ).…”

Section: Immune Responses During Acute Liver Injurymentioning

confidence: 99%

The multifaceted role of macrophages during acute liver injury

Hassan,

Flores Molina,

Shoukry

2023

Front. Immunol.

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The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.

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Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice

Cited by 19 publications

References 64 publications

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC⁺CD63⁺ Endothelial Cells, MMP12⁺ Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury

The multifaceted role of macrophages during acute liver injury

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Dose-dependent pleiotropic role of neutrophils during acetaminophen-induced liver injury in male and female mice

Cited by 19 publications

References 64 publications

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure

Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC+CD63+ Endothelial Cells, MMP12+ Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury

The multifaceted role of macrophages during acute liver injury

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Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC⁺CD63⁺ Endothelial Cells, MMP12⁺ Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury