Biology subjects

Bode, J. G.

Publications and source records attributed to Bode, J. G..

3 recordsLinked to original sources

bioRxiv2025

Immunoglobulin G binding as a quantitative marker of hepatocellular death across acute and chronic liver injury

Background & AimsAccurate detection of hepatocellular death is fundamental for understanding liver injury, intoxication, regeneration, and fibrosis. Conventional markers, such as serum transaminases and histopathological scoring, suffer from limited temporal resolution, high variability, and observer dependence. We evaluated immunoglobulin G (IgG) binding as a quantitative and spatially resolved marker of hepatocyte death in acute and chronic liver injury models. MethodsMale C57BL/6 mice were subjected to acute carbon tetrachloride (CCl) intoxication (1600 mg/kg, single dose), dose-escalation (0-800 mg/kg), and chronic injury paradigms including Western diet (WD), WD+CCl, and Mdr2-/- mice with or without a single CCl challenge. The serum ALT and AST levels were measured. Liver sections were stained with IgG, Hematoxylin and Eosin (H&E), bromodeoxyuridine (BrdU), glutamine synthetase (GS), CD26, and alpha-smooth muscle actin (Acta2). Spatial and integrative transcriptomic analyses were performed to characterize the IgG hepatocyte dead regions. ResultsHepatocellular IgG labeling emerged as early as 6h post-CCl, peaked at 72-96h, and declined during regeneration. IgG-positive areas correlated strongly with Ishak necroinflammatory score (r=0.70) and serum transaminase levels (p=0.74-0.85), surpassing both in Receiver Operating Characteristic (ROC) analyses (AUC=0.92-0.95). IgG bound to both apoptotic (TUNEL) and necrotic (TUNEL-) hepatocytes. In chronic liver injury models, IgG deposition was localized to the injury zones and correlated with ALT/AST, irrespective of etiology. Multiplex imaging revealed IgG-positive necrotic cores surrounded by proliferating hepatocytes and Acta2+ myofibroblasts. Spatial transcriptomics identified immune cell enrichment, Fc{gamma}R-mediated signaling, phagocytosis, and vascular remodeling within the IgG-marked regions. ConclusionsIgG immunostaining provides a robust, quantitative, and pathologist-independent readout of hepatocellular death, which scales with injury severity, delineates necrotic zones, and reveals immune-active microenvironments. These findings establish IgG-based detection as a versatile, high-resolution tool for assessing liver injury, regeneration, and fibrosis. Conflict of Interest declarationThe authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/690787v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1d9b05eorg.highwire.dtl.DTLVardef@ca2ad8org.highwire.dtl.DTLVardef@c2d384org.highwire.dtl.DTLVardef@cca46d_HPS_FORMAT_FIGEXP M_FIG C_FIG Liver injury induced by toxins, dietary stress, or genetic knockout provokes chemokine release (i.e. CXCL1, CXCL2, and CCL3) and recruitment of immune cells, including T cells, NK cells (NKs), and dendritic cells (DCs). Activated immune cells secrete IgG, which binds to damaged hepatocytes, leading to IgG deposition and opsonization. Opsonized hepatocytes expose "eat me" signals, promoting their phagocytic clearance and contributing to the resolution of liver injury and restoration of hepatic homeostasis.

cell biology↗

bioRxiv2024

The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD

Metabolic dysfunction-associated steatotic liver disease is an increasingly prevalent condition, representing a major risk factor for the development of progressive chronic liver damage. This can potentially give rise to the development of steatohepatitis and hepatocellular carcinoma (HCC). It is already known, that patients with metabolic dysfunction-associated steatotic liver disease (MASLD) show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting involvement of ferroptotic cell death in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD. The aim of this study was to determine whether a liver parenchymal cell specific conditional deletion of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) can ameliorate the onset and progression of MASLD in mice. To this end, ACSL4LPC-KO and floxed wild-type littermates were fed a choline-deficient high-fat diet over the course of 20 and 40 weeks to monitor the progression of metabolic liver injury as well as the development of metabolic syndrome. In contrast to the recently published studies by Duan et al. [1], our results show no significant differences between ACSL4LPC-KO and WT mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (i.e. weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response. Our analyses therefore suggest that loss of ACSL4 has no effect on the progression of MASLD induced by choline-deficient high fat diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with liver parenchymal cell specific ACSL4 null mice should be taken with caution.

systems biology↗

bioRxiv2020

Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses

The induction of an interferon-mediated response is the first line of defense against pathogens such as viruses. Yet, the dynamics and extent of interferon alpha (IFN)-induced antiviral genes vary remarkably and comprise three expression clusters: early, intermediate and late. By mathematical modeling based on time-resolved quantitative data, we identified mRNA stability as well as a negative regulatory loop as key mechanisms endogenously controlling the expression dynamics of IFN-induced antiviral genes in hepatocytes. Guided by the mathematical model, we uncovered that this regulatory loop is mediated by the transcription factor IRF2 and showed that knock-down of IRF2 results in enhanced expression of early, intermediate and late IFN-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFN-induced antiviral genes can be mimicked by co-application of IFN and interleukin1 beta (IL1{beta}). Consistently, we found that IL1{beta} enhances IFN-mediated repression of viral replication. Conversely, we observed that in IL1{beta} receptor knock-out mice replication of viruses sensitive to IFN is increased. Thus, IL1{beta} is capable to potentiate IFN-induced antiviral responses and could be exploited to improve antiviral therapies. Author SummaryInnate immune responses contribute to the control of viral infections and the induction of interferon alpha (IFN)-mediated antiviral responses is an important component. However, IFN induces a multitude of antiviral response genes and the expression dynamics of these genes can be classified as early, intermediate and late. Here we show, based on a mathematical modeling approach, that mRNA stability as well as the negative regulator IRF2 control the expression dynamics of IFN-induced antiviral genes. Knock-down of IRF2 resulted in the amplified IFN-mediated induction of the antiviral genes and this amplified expression of antiviral genes could be mimicked by co-stimulation with IFN and IL1{beta}. We observed that co-stimulation with IFN and IL1{beta} enhanced the repression of virus replication and that knock-out of the IL1 receptor in mice resulted in increased replication of a virus sensitive to IFN. In sum, our studies identified IL1{beta} as an important amplifier of IFN-induced antiviral responses.

systems biology↗