Kupffer Cells Research Articles

Multi-omic molecular characterization and diagnostic biomarkers for occult hepatitis B infection and HBsAg-positive hepatitis B infection

BackgroundThe pathological and physiological characteristics between HBsAg-positive HBV infection and occult hepatitis B infection (OBI) are currently unclear. This study aimed to explore the immune microenvironment in the peripheral circulation of OBI patients through integration of proteomic and metabolomic sequencing, and to identify molecular biomarkers for clinical diagnosis of HBsAg-positive HBV and OBI.MethodsThis research involved collection of plasma from 20 patients with OBI (negative for HBsAg but positive for HBV DNA, with HBV DNA levels < 200 IU/mL), 20 patients with HBsAg-positive HBV infection, and 10 healthy individuals. Mass spectrometry-based detection was used to analyze the proteome, while nuclear magnetic resonance spectroscopy was employed to study the metabolomic phenotypes. Differential molecule analysis, pathway enrichment and functional annotation, as well as weighted correlation network analysis (WGCNA), were conducted to uncover the characteristics of HBV-related liver disease. Prognostic biomarkers were identified using machine learning algorithms, and their validity was confirmed in a larger cohort using enzyme linked immunosorbent assay (ELISA).ResultsHBsAg-positive HBV individuals showed higher ALT levels (p=0.010) when compared to OBI patients. The influence of HBV infection on metabolic functions and inflammation was evident through the analysis of distinct metabolic pathways in HBsAg-positive HBV and OBI groups. Tissue tracing demonstrated a connection between Kupffer cells and HBsAg-positive HBV infection, as well as between hepatocytes and OBI. Immune profiling revealed the correlation between CD4 Tem cells, memory B cells and OBI, enabling a rapid response to infection reactivation through cytokine secretion and antibody production. A machine learning-constructed and significantly expressed molecule-based diagnostic model effectively differentiated HBsAg-positive and OBI groups (AUC values > 0.8). ELISA assay confirmed the elevation of FGB and FGG in OBI samples, suggesting their potential as biomarkers for distinguishing OBI from HBsAg-positive infection.ConclusionsThe immune microenvironment and metabolic status of HBsAg-positive HBV patients and OBI patients vary significantly. The machine learning-based diagnostic model described herein displayed impressive classification accuracy, presenting a non-invasive means of differentiating between OBI and HBsAg-positive HBV infections.

Reprogramming macrophages to treat liver diseases

Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or hepatocellular carcinoma. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role on both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue Kupffer cells and monocyte-derived macrophages) display such plasticity and phenotypic diversity that macrophages with antagonistic functions may coexist in adjacent regions of the liver. In this scenario, the analysis of macrophage-derived inflammatory and anti-inflammatory circulating soluble markers in patients with liver disease only offers a partial picture of the full complexity of the hepatic macrophage subsets. The reprogramming of macrophages involves understanding the multiple regulatory mechanisms and diverse populations of hepatic macrophages and the design of macrophage-targeted therapeutic interventions to restore hepatic homeostasis. Here we review the potential targets to modulate macrophage behavior in liver diseases and nanoscale therapeutics that aim to target and treat macrophages. We will summarize current knowledge on the diverse macrophage programs activated in chronic liver inflammation, cirrhosis and hepatocellular carcinoma that may be of therapeutic interest for precision medicine.

IMMUNE DYSREGULATION IN AUTOIMMUNE HEPATITIS: THE ROLE OF AUTOANTIBODIES, T-REG CELLS, AND NOVEL THERAPEUTIC APPROACHES

Introduction. The liver is a crucial immunological tolerogenic organ with a unique ability to generate effective immune responses against hepatotropic pathogens while maintaining both local and systemic immune tolerance to self and foreign antigens. Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease caused by the loss of tolerance to liver-specific antigens, leading to autoimmune liver damage.Aim – to summarize current knowledge on the immunopathogenesis of AIH based on information from open sources.Material and methods. The selection of publications was conducted using databases such as PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection, and Google Scholar, which covered information on the immunopathogenesis of AIH. Literature search was performed using keywords: autoimmune diseases, autoimmune hepatitis, Kupffer cells, autoantibodies to liver microsomal antibodies, and mesenchymal stem cells.Research results. Liver immune regulation is mediated by unique cell populations, including T-reg cells, Kupffer cells, and NK cells, which interact to maintain immune tolerance and regulate inflammation. Deficiency or dysfunction of T-reg cells, along with the activation of Th17 cells, contribute to the development of inflammatory processes and autoimmune liver damage. The quantitative and qualitative composition of immune cells in the liver differs significantly from that in secondary lymphoid organs, such as lymph nodes, spleen, or peripheral blood. The CD8+/CD4+ ratio (3.5:1) of liver T cells contrasts with the 1:2 ratio observed in peripheral blood, lymph nodes, and spleen.Conclusions. AIH is a complex disease with a multifaceted immunopathogenesis. T-reg and MSC-based therapies show promising results in clinical trials; however, further research is needed to optimize these methods and ensure their safe and effective application.

The possible protective effect of luteolin on cardiovascular and hepatic changes in metabolic syndrome rat model.

The metabolic syndrome, or MetS, is currently a global health concern. The anti-inflammatory, anti-proliferative, and antioxidant properties of luteolin are some of its advantageous pharmacological characteristics. This research was designed to establish a MetS rat model and investigate the possible protective effect of luteolin on cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. Forty adult male albino rats were split into four groups: a negative control group, a group treated with luteolin, a group induced MetS (fed 20% fructose), and a group treated with luteolin (fed 20% fructose and given luteolin). Following the experiment after 8weeks, biochemical, histological (light and electron), and immunohistochemistry analyses were performed on liver and heart tissues. Serum levels of cTnI, CK-MB, and LDH were significantly elevated in response to the cardiovascular effect of MetS. Furthermore, compared to the negative control group, the MetS group showed a marked increase in lipid peroxidation in the cardiac and hepatic tissues, as evidenced by elevated levels of MDA and a decline in the antioxidant defense system, as demonstrated by lower activities of GSH and SOD. The fatty liver-induced group exhibited histological alterations, including disrupted hepatic architecture, dilated and congested central veins, blood sinusoids, and portal veins. In addition to nuclear structural alterations, most hepatocytes displayed varying degrees of cytoplasmic vacuolation, mitochondrial alterations, and endoplasmic reticulum dilatation. These alterations were linked to inflammatory cellular infiltrations, collagen fiber deposition, active hepatic stellate cells, and scattered hypertrophied Kupffer cells, as demonstrated by electron microscopy and validated by immunohistochemical analysis. It is interesting to note that eosinophils were seen between the liver cells and in dilated blood sinusoids. Moreover, the biochemical (hepatic and cardiac) and histological (liver) changes were significantly less severe in luteolin-treated raton a high-fructose diet.These results suggested that luteolin protects against a type of metabolic syndrome that is produced experimentally.

Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.

Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.

Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation.

Migracytosis is a recently described cellular process that generates and releases membrane-bound pomegranate-like organelles called migrasomes. Migracytosis normally occurs during cell migration, participating in various intercellular biological functions. Here, we report a new type of migracytosis induced by small GTPase-targeting toxins. Unlike classic migracytosis, toxin-induced migrasome formation does not rely on cell migration and thus can occur in both mobile and immobile cells. Such non-canonical migracytosis allows the cells to promptly respond to microbial stimuli such as bacterial toxins and effectors and release informative cellular contents in bulk. We demonstrated that C. difficile TcdB3 induces liver endothelial cells and Kupffer cells to produce migrasomes in vivo. Moreover, the migracytosis-defective Tspan9‒/‒ mice show less acute inflammation and lower lethality rate in the toxin challenge assay. Therefore, we propose that the non-canonical migracytosis acts as a new mechanism for mammalian species to sense and exacerbate early immune response upon microbial infections.

N6-methyladenosine modification of circDcbld2 in Kupffer cells promotes hepatic fibrosis via targeting miR-144-3p/Et-1 axis

Kupffer cells (KCs), as residents and sentinels of the liver, are involved in the formation of hepatic fibrosis (HF). However, the biological functions of circular RNAs (circRNAs) in KCs to HF have not been determined. In this study, the expression levels of circRNAs, microRNAs, and messenger RNAs (mRNAs) in KCs from a mouse model of HF mice were investigated using microarray and circRNA-Seq analyses. circDcbld2 was identified as a candidate circRNA in HF, as evidenced by its up-regulation in KCs. Silver staining and mass spectrometry showed that Wtap and Igf2bp2 bind to cirDcbld2. The suppression of circDcbld2 expression decreased the KC inflammatory response and oxidative stress and inhibited hepatic stellate cell (HSCs) activation, attenuating mouse liver fibrogenesis. Mechanistically, Wtap mediated the N6-methyladenosine (m6A) methylation of circDcbld2, and Igf2bp2 recognized m6A-modified circDcbld2 and increased its stability. circDcbld2 contributes to the occurrence of HF by binding miR-144-3p/Et-1 to regulate the inflammatory response and oxidative stress. These findings indicate that circDcbld2 functions via the m6A/circDcbld2/miR-144-3p/Et-1 axis and may act as a potential biomarker for HF treatment.

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.

Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells

Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state.

HMGB1/TREM1 crosstalk between heat-injured hepatocytes and macrophages promotes HCC progression after RFA

PurposeTumor recurrence after radiofrequency ablation (RFA) affects the survival rate of patients and limits its clinical application. Tumor recurrence around the ablation area may be related to the thermal injury of hepatocytes (HCs) around the tumor, but the specific mechanism is still unclear.MethodsA liver cancer thermal injury mouse model was established via RFA in the C57BL/6 mice. Primary HCs and Kupffer cells (KCs) were isolated and cultured to assess their sensitivity to thermal injury via the MTT assay. Flow cytometry was used to assess macrophage polarization. Furthermore, Western blotting and co-immunoprecipitation (co-IP) were utilized to evaluate the protein expression of intracellular signaling pathway. Finally, Transwell and wound healing assays was conducted to evaluate the invasion potential of liver cancer cells.ResultsOur findings revealed that RFA-induced liver thermal injury promoted the upregulation and secretion of HMGB1 in HCs. HMGB1 had a protective effect on HCs thermal injury, potentially mediated through autophagy regulation. Heat-injured HCs release HMGB1, which activates the TREM1/JAK2/STAT3 signaling pathway in KCs, thus fostering an immunosuppressive tumor microenvironment (TME). Moreover, HMGB1 secretion by heat-injured HCs exacerbates the migration and invasion of HCC cells by influencing macrophage polarization.ConclusionRFA-induced thermal injury triggers HMGB1 release from HCs, driving macrophage M2 polarization and increasing the invasion ability of liver cancer cells. These findings reveal a potential therapeutic target for combating liver cancer recurrence following thermal ablation.

Platelet Glycoprotein Ibα Cytoplasmic Tail Exacerbates Thrombosis During Bacterial Sepsis.

Septic patients, coupling severe disseminated intravascular coagulation (DIC) and thrombocytopenia, have poor prognoses and higher mortality. The platelet glycoprotein Ibα (GPIbα) is involved in thrombosis, hemostasis, and inflammation response. However, it remains unclear whether the GPIbα cytoplasmic tail regulates sepsis-mediated platelet activation and inflammation, especially in Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections. Using a mouse model of S. aureus-induced bacteremia, we found that both 10 amino acids of GPIbα C-terminal sequence deficiency and pharmacologic inhibition of protein kinase C (PKC) alleviated pathogenesis by diminishing platelet activation and aggregate formation. Furthermore, the GPIbα cytoplasmic tail promoted the phagocytosis of platelets by Kupffer cells in vivo. The genetically deficient GPIbα cytoplasmic tail also downregulated inflammatory cytokines and reduced liver damage, ultimately improving the survival rate of the septic mice. Our results illustrate that the platelet GPIbα cytoplasmic domain exacerbates excessive platelet activation and inflammation associated with sepsis through a PKC-dependent pathway. Thus, our findings provide insights for the development of effective therapeutic strategies using PKC inhibitor treatment against bacterial infection.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health.

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice.

Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.

Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis.

To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis. Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq. Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis. This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

Correlation Between Thrombin Generation and Hepatic Fibrosis in Chronic Liver Diseases.

Hepatic stellate cells (HSC) are recruited to the siteof injury in the liver tissue repair mechanism, and the changes HSC undergo reflect paracrine stimulation by all cell types (sinusoidal endothelial cells, Kupffer cells, hepatocytes, platelets, and leukocytes). This study aimed to analyse a possible correlation between the degree of liver fibrosis and thrombin generation in patients with chronic liver diseases. Background Coagulation disorders in patients with chronic liver disease continue to challenge clinicians. A more accurate assessment of the coagulation cascade is provided by investigating thrombin production in individuals with chronic liver disease with varying degrees of fibrosis. Methods This prospective observational pilot study was done on hospitalized patients with chronic liver diseases.Thrombin generation from their platelet-poor plasma was studied and the degree of liver fibrosis assessed by transient elastography versus that of control subjects. Results The peak thrombin is significantly higher in those with severe liver stiffness (F3) than in those with more advanced fibrosis/liver cirrhosis (F4). Also, the total concentration of thrombin formed in the time interval (area under the curve (AUC)) and velocity index (VI) is higher in those with F3 than those with F4. Conclusion Thrombin generation decreases with the progression of liverfibrosis.

Immunoexpression of CD34, CD68 and CD3 in Cadmium-Induced Liver Damage and Protective Effectiveness of Bee Bread (Perga)

Cadmium (Cd) is one of the potent environmental toxicants that causes oxidative stress in many organs of the body, including the liver. Perga (bee bread) is used for apitherapeutic purposes due to its medicinal properties. This study was conducted to investigate the effectiveness of perga on endothelial damage and inflammatory cell activation in the liver as a result of exposure to Cd. For this purpose, 32 male Wistar rats (8 rats/group) were randomly divided into 4 groups, as the control, perga (0.5 g/kg of perga), Cd (5 mg/kg of CdCl2), and Cd + perga (0.5 g/kg of perga + 5 mg/kg of CdCl2) groups. Daily intragastric Cd and/or perga was administered for 4 weeks. At the end of the study, the rats were euthanized and liver tissue sections were taken and stained with hematoxylin-eosin and Masson’s Trichrome. Immunohistochemically, the reactivity of the liver sinusoidal endothelium was determined using CD34, the reactivity of the Kupffer cells was determined using CD68, and the levels of T-lymphocyte cells were determined using CD3 antibodies. Exposure to Cd caused significant histological changes in the liver. Immunohistochemically, exposure to Cd caused an increase in the expressions of CD34, CD68, and CD3. On the other hand, the cotreatment of Cd and perga caused partial improvement in some histopathological changes. Compared to the Cd group, there was a decrease in CD34 and CD68 positivity in the Cd + perga group, while no significant difference was detected in the number of CD3-positive cells between the groups. The results revealed that the histopathological changes and inflammation in the rat liver could partially improve with perga supplementation.

A historical perspective of Kupffer cells in the context of infection.

The Kupffer cell was first discovered by Karl Wilhelm von Kupffer in 1876, labeling them as "Sternzellen." Since their discovery as the primary macrophages of the liver, researchers have gradually gained an in-depth understanding of the identity, functions, and influential role of Kupffer cells, particularly in infection. It is becoming clear that Kupffer cells perform important tissue-specific functions in homeostasis and disease. Stationary in the sinusoids of the liver, Kupffer cells have a high phagocytic capacity and are adept in clearing the bloodstream of foreign material, toxins, and pathogens. Thus, they are indispensable to host defense and prevent the dissemination of bacteria during infections. To highlight the importance of this cell, this review will explore the history of the Kupffer cell in the context of infection beginning with its discovery to the present day.

Therapeutic Potential of Nutraceuticals against Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) continues to be a major concern in clinical practice, thus necessitating a need for novel therapeutic approaches to alleviate its impact on hepatic function. This review investigates the therapeutic potential of nutraceuticals against DILI, focusing on examining the underlying molecular mechanisms and cellular pathways. In preclinical and clinical studies, nutraceuticals, such as silymarin, curcumin, and N-acetylcysteine, have demonstrated remarkable efficacy in attenuating liver injury induced by diverse pharmaceutical agents. The molecular mechanisms underlying these hepatoprotective effects involve modulation of oxidative stress, inflammation, and apoptotic pathways. Furthermore, this review examines cellular routes affected by these nutritional components focusing on their influence on hepatocytes, Kupffer cells, and stellate cells. Key evidence highlights that autophagy modulation as well as unfolded protein response are essential cellular processes through which nutraceuticals exert their cytoprotective functions. In conclusion, nutraceuticals are emerging as promising therapeutic agents for mitigating DILI, by targeting different molecular pathways along with cell processes involved in it concurrently.

Complement 3a Receptor 1 on Macrophages and Kupffer cells is not required for the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MjKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MjKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3aR1 , has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.