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Immunological players in the liver The liver lobule, the functional unit of the organ, is composed of a portal triad, a capillary network lined by hepatocytes, and a central vein. Zone 1 represents the periportal region, consisting of the portal triad that is made up of the hepatic artery, the hepatic portal vein, and the bile duct. Zone 2 represents the interzonal region, and Zone 3 consists of the pericentral region. The cellular composition of the liver can be categorized as parenchymal cells (hepatocytes) and non-parenchymal cells, including cholangiocytes, hepatic stellate cells, endothelial cells, and immune cells. Almost all types of immune cells can be found in the liver tissue. These immune cells include phagocytes (macrophages, DCs, and neutrophils) and lymphocytes (innate lymphoid cells, T cells, and B cells). Many of these populations currently lack confirmation and consensus regarding their location and definitive frequencies in the liver, thus most of their distribution remains speculative. Abbreviations: DC, dendritic cell; ILC, innate lymphoid cell (type 1, 2, and 3); MAIT, mucosal associated invariant T cell; NK cell, natural killer cell; NKT, natural killer T cell; Th1, type 1 helper T cell; Th2, type 2 helper T cell; Th17, type 17 helper T cell; Th22, type 22 helper T cell; Treg, regulatory T cell.
Source publication
The liver is an essential organ that is critical for the removal of toxins, the production of proteins, and the maintenance of metabolic homeostasis. Behind each liver functional unit, termed lobules, hides a heterogeneous, complex, and well-orchestrated system. Despite parenchymal cells being most commonly associated with the liver’s primary funct...
Contexts in source publication
Context 1
... functional unit of the liver, termed the hepatic lobule, is composed of parenchymal cells (hepatocytes) and cholangiocytes, lined with liver sinusoidal endothelial cells (LSECs). These hexagonal lobules contain liver sinusoids that extend from the central vein at the center of the lobule to the portal triads distributed at its vertices, which consist of branches of the hepatic artery, portal vein, and bile duct (Figure 1). With approximately 75% of its blood supplied by the portal vein, the liver is continuously exposed to gut-derived molecules, including pathogens, commensals, and food antigens. ...
Context 2
... recently, particular attention has been paid to the role that the hepatic immune niche has in liver homeostasis, inflammation and regeneration, and how new omics technologies can help uncover this interplay, a topic which is the main focus of this review. Figure 1 summarizes the types of immune cells that have been described in the human liver and the putative locations of these cells in reference to the hepatic sinusoid. Despite the significant advances in our understanding of the liver, studies have only just begun to tease out the distinct contributions and unique phenotypes of different liver-resident parenchymal and non-parenchymal cells. ...
Context 3
... liver is enriched with cells of the innate and adaptive immune systems that maintain tolerance in a homeostatic state and can mediate inflammation and hepatic injury in disease (Figure 1). Adaptive immune cells that are found in the liver include T cells, such as regulatory T cells (Tregs), cytotoxic T lymphocytes (CTLs) and Type 1, 2, 17 and 22 helper T cells (T h 1, T h 2, T h 17, and T h 22) [11][12][13], in addition to B cell and plasma cell populations. ...
Citations
... A limitation was the lack of flow cytometry to examine the sub-types of macrophages and T cells; however, this procedure has to be planned and coordinated at the end of the feeding trial, as fresh adipose tissue is required to isolate the stromal vascular fraction and to label immune cells with the appropriate combinations of fluorescent antibodies for a flow cytometric analysis. The differential effects of EPA and DHA on immune cells in adipose tissue of the present study, and our previous report of the divergent effects of EPA and DHA on hepatic steatosis [35] indicate that future studies investigating the effects of EPA and DHA on immune cell subtypes need to extend beyond the adipose tissue and obesity to the liver and hepatic steatosis [80] as well as other organs relevant to chronic disease conditions. ...
Polyunsaturated fatty acids (PUFAs) can alter adipose tissue function; however, the relative effects of plant and marine n3-PUFAs are less clear. Our objective was to directly compare the n3-PUFAs, plant-based α-linolenic acid (ALA) in flaxseed oil, and marine-based eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in high-purity oils versus n6-PUFA containing linoleic acid (LA) for their effects on the adipose tissue and oral glucose tolerance of obese rats. Male fa/fa Zucker rats were assigned to faALA, faEPA, faDHA, and faLA groups and compared to baseline fa/fa rats (faBASE) and lean Zucker rats (lnLA). After 8 weeks, faEPA and faDHA had 11–14% lower body weight than faLA. The oral glucose tolerance and total body fat were unchanged, but faEPA had less mesenteric fat. faEPA and faDHA had fewer large adipocytes compared to faLA and faALA. EPA reduced macrophages in the adipose tissue of fa/fa rats compared to ALA and DHA, while faLA had the greatest macrophage infiltration. DHA decreased (~10-fold) T-cell infiltration compared to faBASE and faEPA, whereas faALA and faLA had an ~40% increase. The n3-PUFA diets attenuated tumour necrosis factor-α in adipose tissue compared to faBASE, while it was increased by LA in both genotypes. In conclusion, EPA and DHA target different aspects of inflammation in adipose tissue.
... While the relationship of AAC and NAFLD has been described, evidence supporting the associations of AAC with other liver diseases and clinical outcomes is relatively sparse and may be overlooked [6]. The liver is a central organ supporting homeostasis, metabolism, immunity, digestion, and detoxification [24,25]. Modification of lipid and glucose metabolism are common factors of both cardiovascular disease and liver disease [26][27][28][29]. ...
Introduction
Abdominal aortic calcifications (AAC) are incidentally found on medical imaging and useful cardiovascular burden approximations. The Morphomic Aortic Calcification Score (MAC) leverages automated deep learning methods to quantify and score AACs. While associations of AAC and non-alcoholic fatty liver disease (NAFLD) have been described, relationships of AAC with other liver diseases and clinical outcome are sparse. This study’s purpose was to evaluate AAC and liver-related death in a cohort of Veterans with chronic liver disease (CLD).
Methods
We utilized the VISN 10 CLD cohort, a regional cohort of Veterans with the three forms of CLD: NAFLD, hepatitis C (HCV), alcohol-associated (ETOH), seen between 2008 and 2014, with abdominal CT scans (n = 3604). Associations between MAC and cirrhosis development, liver decompensation, liver-related death, and overall death were evaluated with Cox proportional hazard models.
Results
The full cohort demonstrated strong associations of MAC and cirrhosis after adjustment: HR 2.13 (95% CI 1.63, 2.78), decompensation HR 2.19 (95% CI 1.60, 3.02), liver-related death HR 2.13 (95% CI 1.46, 3.11), and overall death HR 1.47 (95% CI 1.27, 1.71). These associations seemed to be driven by the non-NAFLD groups for decompensation and liver-related death [HR 2.80 (95% CI 1.52, 5.17; HR 2.34 (95% CI 1.14, 4.83), respectively].
Discussion
MAC was strongly and independently associated with cirrhosis, liver decompensation, liver-related death, and overall death. Surprisingly, stratification results demonstrated comparable or stronger associations among those with non-NAFLD etiology. These findings suggest abdominal aortic calcification may predict liver disease severity and clinical outcomes in patients with CLD.
... Senescent cells accumulate in tissues and organs, ultimately leading to their dysfunction and aging. The liver is the body's largest digestive gland and an important metabolic immune, with various functions, including protein synthesis, glycogen storage, and detoxification (Cheng et al., 2021;Kubes and Jenne, 2018). Aging has a particularly significant impact on the liver, as a large number of free radicals can induce hepatocyte degeneration, apoptosis, and even necrosis (Azman et al., 2021). ...
... Enhanced computed tomography (CT) scans of the liver have gained widespread use as a common diagnostic and examination method for liver diseases due to their high lesion detection rate. However, the liver has a dual blood supply system through the portal vein and hepatic artery (1,2). Consequently, a 3-phase scan is used in liver enhancement examinations, leading to an increased number of scans and higher radiation doses for patients. ...
Background: During computed tomography (CT) examinations, the presence of radiation material undoubtedly has a certain impact on patients, particularly children, who are more susceptible to radiation. Consequently, finding ways to minimize radiation dosage and mitigate radiation-related risks while enhancing the quality and accuracy of CT scans has become a crucial concern for medical professionals in CT equipment manufacturing companies and radiology departments to contemplate. Objectives: This study aimed to explore the feasibility of low dose and low contrast medium combined with low flow rate scanning in CT angiography (CTA) of children's liver. Patients and Methods: A total of 59 children who visited our department for liver vascular CT scans between April 2021 and December 2022 were prospectively selected and randomly divided into 2 groups: the experimental group and the control group. The experimental group consisted of 28 children who received an injection of 80 kV, automatic tube current, low contrast dose (1.5 mL/kg), and low flow rate of 20 s. The control group included 31 children who were injected with 100 kV, automatic tube current, contrast agent dose (2 mL/kg), and flow rate of 16 s. The objective and subjective image quality, radiation dose, and iodine intake in the arterial, portal, and venous phases were compared between the 2 groups. Results: During the arterial, portal, and venous phases, the experimental group exhibited lower signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) compared to the control group (P < 0.05). However, there was no significant difference in subjective quality scores between the 2 groups (P > 0.05). The effective dose (ED), volume CT dose index (CTDIvol), and dose-length product (DLP) of the experimental group were lower than those of the control group (P < 0.05). Additionally, the iodine intake in the experimental group was lower than that in the control group (P < 0.05). Conclusion: In the examination of hepatic vascular CTA in children, the use of a 3-low scanning technique can effectively decrease radiation and contrast agents while ensuring sufficient image quality for accurate clinical diagnosis.
... The liver functions as a frontline immune organ strategically positioned to detect and clear pathogens entering the body through the gut, underscoring its significant role in the immune response (Loor et al., 2005;Yan et al., 2014). Notably, variations in the expression of immune-related genes in this organ can profoundly affect metabolic function, nutrient availability, and feed efficiency in animals (Vigors et al., 2019;Cheng et al., 2021). Thus, in this study, we hypothesized that the expression of some immunity genes would vary in beef steers with divergent positive or negative RADG. ...
Immune function plays a pivotal role in dictating the overall health and productivity of cattle. In a proficient immune system, the liver assumes an integral function in detoxification and metabolic processes and contributes substantially to overall production and immunity. In this study, we evaluated the hepatic mRNA expression of genes involved in innate and adaptive immunity in crossbred beef steers with positive or negative residual body weight gain (RADG). Positive-RADG beef steers (n = 8; RADG = 0.73 kg/d) and negative-RADG beef steers (n = 8; RADG =-0.69 kg/d) were identified from a group of 108 growing crossbred beef steers (average BW = 556 ± 38 kg) after a 56-d performance testing period. At the end of the 56-d period, liver tissue samples were collected from the beef steers for RNA extraction and cDNA synthesis. The mRNA expression of 84 genes involved in innate and adaptive immunity were analyzed using pathway-focused PCR-based arrays. The mRNA expression of genes with false discovery rate-adjusted P-values (FDR) ≤ 0.05 and absolute fold change (FC) ≥ 1.2 were determined to be differentially expressed. Out of the 84 genes analyzed, four genes (IL-2, MYD88, CD-80, NFkB-1) were differentially expressed and were all upregulated in positive compared with negative-RADG beef steers. IL-2 is a cytokine that plays a critical role in the immune response by activating and proliferating T-cells, which are important for fighting infections. MYD88 is an adaptor protein that is essential for signaling by toll-like receptors, which are involved in pathogen recognition. CD80 is a protein that is expressed on the surface of antigen-presenting cells and plays a critical role in the initiation of an immune response. The activation of NF-kB leads to the production of cytokines and chemokines that help to recruit immune cells to the site of infection. The upregulation of the aforementioned genes in positive-RADG beef steers suggests that they had a better ability than negative-RADG beef steers to quickly recognize pathogens and initiate appropriate responses to effectively fight off infections without causing inflammatory reactions, potentially contributing to their better feed efficiency.
... Despite a slight slowdown in recent years, this upward trend remains concerning. The development of hepatic tumors not only impacts the patient's digestive and immune systems but also causes significant pain (Cheng et al. 2021). Consequently, the search for effective treatments for liver cancer has been a longstanding objective for medical practitioners and scientists. ...
A meta-analysis was performed to assess the benefits and safety profile of approved immune checkpoint inhibitors in hepatocellular carcinoma patients. Eligible studies were searched from Cochrane, Embase, and PubMed databases based on a well-established strategy. Following the exclusion of ineligible studies, 12 studies were included in this meta-analysis. Compared with control group, immune checkpoint inhibitors were associated with improved ORR (OR 3.03, 95% CI 2.26–4.05, P < 0.00001), SD (OR 0.77, 95% CI 0.62–0.95, P = 0.02), OS (HR 0.75, 95% CI 0.68–0.83, P < 0.00001), and PFS (HR 0.74, 95% CI 0.63–0.87, P < 0.0003). However, no significant differences were observed in DCR (OR 1.33, 95% CI 0.97–1.81, P = 0.07), PD (OR 0.90, 95% CI 0.67–1.21, P = 0.48), and all caused any-grade adverse events (OR 1.22, 95% CI 0.62–2.39, P = 0. 57), all caused ≥ grade 3 adverse events (OR 1.10, 95% CI 0.97–1.25, P = 0.14), treatment-related any-grade adverse events (OR 1.13, 95% CI 0.55–2.32, P = 0.73), and treatment-related ≥ grade 3 events (OR 0.82, 95% CI 0.34–1.97, P = 0.65) between the two groups. After subgroup analysis conducted, patients in the immune checkpoint inhibitor group compared with targeted drug group showed significant improvements in OS (HR 0.74, 95% CI 0.66–0.84, P < 0.00001) and PFS (HR 0.75, 95% CI 0.61–0.91, P = 0.004). Immune checkpoint inhibitors have demonstrated peculiar benefits in the treatment of HCC with an acceptable safety profile. Compared to targeted drugs, immune checkpoint inhibitors still offer advantages in the treatment of hepatocellular carcinoma. However, there is still considerable room for further improvement.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00432-023-05539-8.
... The liver, an essential organ within the immune system, plays a pivotal role by filtering and processing blood, making it a central hub for immune-related activities. Furthermore, the liver serves as a key site for immune cell interactions, the initiation of immune responses, and the establishment of immune tolerance (7). Moreover, the liver is the organ with the highest number of macrophages among solid organs, accounting for approximately 90% of the total macrophage count in the body. ...
Macrophages play a critical role in innate immunity, with approximately 90% of the total macrophage population in the human body residing in the liver. This population encompasses both resident and infiltrating macrophages. Recent studies highlight the pivotal role of liver macrophages in various aspects such as liver inflammation, regeneration, and immune regulation. A novel pro-inflammatory programmed cell death, pyroptosis, initially identified in macrophages, has garnered substantial attention since its discovery. Studies investigating pyroptosis and inflammation progression have particularly centered around macrophages. In liver diseases, pyroptosis plays an important role in driving the inflammatory response, facilitating the fibrotic process, and promoting tumor progression. Notably, the role of macrophage pyroptosis cannot be understated. This review primarily focuses on the role of macrophage pyroptosis in liver diseases. Additionally, it underscores the therapeutic potential inherent in targeting macrophage pyroptosis.
... 3,5,6 Understanding the healthy liver by building a comprehensive reference map with an inventory of cells and their respective spatial localization is crucial in elucidaing the transcriptomic and phenotypic changes, rare cell types, and cell-cell interactions that underlie disease development. 7,8 Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease that is characterized by the retention of bile, destruction of the biliary tree and development of fibrosis. 9 Given the rarity of the disease and the timeline from diagnosis to end-stage liver disease, few studies have attempted to map the PSC liver and characterize its cellular landscape. ...
... The hepatic portal vein serves as a pivotal conduit for the liver, contributing approximately 3/4 of the liver's blood supply. This vessel transports nutrient-laden blood from the gastrointestinal tract to the liver for metabolism (14). The blood, mixed with arterial blood, flows into sinusoidal vessels of the liver. ...
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as “hepatokines”). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body’s innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
... The liver is a vital organ for removing toxins and maintaining metabolic homeostasis. Thus, to some extent, the immune status of the liver reflects the health of the host [50]. Once LPS enters the liver through the bloodstream, the hepatocytes are injured due to the accumulation of LPS in the liver, which in turn leads to an increase in the clearance of LPS in the liver; however, the capacity of the removal is distinctly reduced [51]. ...
Subacute ruminal acidosis (SARA) has been demonstrated to promote the development of mastitis, one of the most serious diseases in dairy farming worldwide, but the underlying mechanism is unclearn. Using untargeted metabolomics, we found hexadecanamide (HEX) was significantly reduced in rumen fluid and milk from cows with SARA-associated mastitis. Herein, we aimed to assess the protective role of HEX in Staphylococcus aureus ( S . aureus )- and SARA-induced mastitis and the underlying mechanism. We showed that HEX ameliorated S . aureus -induced mastitis in mice, which was related to the suppression of mammary inflammatory responses and repair of the blood-milk barrier. In vitro , HEX depressed S . aureus -induced activation of the NF-κB pathway and improved barrier integrity in mouse mammary epitheial cells (MMECs). In detail, HEX activated PPARα, which upregulated SIRT1 and subsequently inhibited NF-κB activation and inflammatory responses. In addition, ruminal microbiota transplantation from SARA cows (S-RMT) caused mastitis and aggravated S . aureus -induced mastitis, while these changes were reversed by HEX. Our findings indicate that HEX effectively attenuates S . aureus - and SARA-induced mastitis by limiting inflammation and repairing barrier integrity, ultimately highlighting the important role of host or microbiota metabolism in the pathogenesis of mastitis and providing a potential strategy for mastitis prevention.
