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Metabolic defects in splenic B cell compartments from patients with liver cirrhosis.

ABSTRACT: Liver cirrhosis is associated with defective vaccine responses and increased infections. Dysregulated B cell compartments in cirrhotic patients have been noticed but not well characterized, especially in the spleen. Here, we comprehensively investigated B cell perturbations from the spleens and peripheral blood of cirrhotic patients. We found that liver cirrhosis significantly depleted both switched and nonswitched splenic memory B cells, which was further confirmed histologically. Bulk RNA-seq revealed significant metabolic defects as the potential mechanism for the impaired splenic B cell functions. Functionally, the splenic memory B cells from cirrhotic patients showed strong metabolic defects and reduced proliferation compared with those from healthy controls. Thus, liver cirrhosis extensively disturbs the splenic and peripheral B cell compartments, which may contribute to defective humoral immunity during liver cirrhosis.

SUBMITTER: Huang M

PROVIDER: S-EPMC7585577 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Metabolic defects in splenic B cell compartments from patients with liver cirrhosis.

Huang Man M Liu Xiaoju X Ye Haocheng H Zhao Xin X Zhao Juanjuan J Liu Yang Y He Xiaomeng X Qu Mengmeng M Pan Jing J Hou Baidong B Cheng Yongqian Y Liu Zhenwen Z Li Zhiwei Z Liu Lei L Sun Jian J Zhang Shuye S Zhang Zheng Z

Cell death & disease 20201024 10

Liver cirrhosis is associated with defective vaccine responses and increased infections. Dysregulated B cell compartments in cirrhotic patients have been noticed but not well characterized, especially in the spleen. Here, we comprehensively investigated B cell perturbations from the spleens and peripheral blood of cirrhotic patients. We found that liver cirrhosis significantly depleted both switched and nonswitched splenic memory B cells, which was further confirmed histologically. Bulk RNA-seq ...[more]

PMID: 33099582

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Project description:Liver cirrhosis (LC) is the final usual outcome of liver damage induced by various chronic liver diseases. Because of asymptomatic nature of LC, it is usually diagnosed at late and advanced stages, and patients are easy to miss the best timing for treatment. Thus, the early detection of LC is needed. In the prospective Korean Cancer Prevention Study-II (K-II), we aimed to identify valuable biomarkers for LC using metabolomics to distinguish subjects with incident LC (LC group) from subjects free from LC (control group) during a mean 7-year follow-up period. Metabolic alterations were investigated using baseline serum specimens acquired from 94 subjects with incident LC and 180 age- and sex-matched LC-free subjects via ultra-performance liquid chromatography (UPLC)-linear-trap quardrupole (LTQ)-Orbitrap mass spectrometry (MS). As a result of the metabolic analysis, 46 metabolites were identified. Among them, 11 and 18 metabolite level showed a significant increase and decrease, respectively, in the LC group compared to the control group. Nine metabolic pathways, including glyoxylate and dicarboxylate metabolism, amino acid metabolism, fatty acid metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism, were significantly different between the two groups. Logistic regression demonstrated that the LC emergence was independently affected by serum levels of myristic acid, palmitic acid, linoleic acid, eicosapentaenoic acid (EPA), lysophosphatidic acid (LPA) (18:1), glycolic acid, lysophosphatidylcholine (lysoPC) (22:6), and succinylacetone (R 2 = 0.837, P < 0.001). This prospective study revealed that dysregulation of various metabolism had the clinical relevance on the LC development. Moreover, myristic acid, palmitic acid, linoleic acid, EPA, LPA (18:1), glycolic acid, lysoPC (22:6), and succinylacetone were emerged as independent variables influencing the incidence of LC. The results support that the early biomarkers found in this study may useful for predicting and remedying the risk of LC.

Project description:Background & aimsLiver stiffness is increased in advanced chronic liver disease (ACLD) and accurately predicts prognosis in this population. Recent data suggest that extracellular matrix stiffness per se may modulate the phenotype of liver cells. We aimed at investigating the effect of matrix stiffness on the phenotype of liver cells of rats with cirrhosis, assessing its influence on their response to antifibrotic strategies and evaluating associated molecular mechanisms.MethodsHepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells were isolated from healthy rats or rats with cirrhosis (carbon tetrachloride or thioacetamide), and cultured on polyacrylamide gels with different physiologically relevant stiffness for 72 h.ResultsAll cell types of rats with cirrhosis cultured at low stiffness showed a significant phenotype amelioration vs. rigid matrix (assessed by quantitative morphology, mRNA expression, protein synthesis, and electron microscopy imaging). Additionally, stiffness modified the antifibrotic effects of liraglutide in stellate cells of rats with cirrhosis. Finally, evaluation of nuclear morphology revealed that high stiffness induced nuclei deformation in all cell types, an observation confirmed in cells from human livers. Disconnecting the nucleus from the cytoskeleton by cytoskeleton disruption or a defective form of nesprin 1 significantly recovered spherical nuclear shape and quiescent phenotype of cells.ConclusionsThe environment's stiffness per se modulates the phenotype of healthy rats and liver cells of rats with cirrhosis by altering the nuclear morphology through cytoskeleton-derived mechanical forces. The reversibility of this mechanism suggests that targeting the stiffness-mediated intracellular mechanical tensions may represent a novel therapeutic strategy for ACLD.Lay summaryDuring cirrhosis, the liver becomes scarred, stiff, and unable to perform its normal functions efficiently. In this study, we demonstrated that cells from diseased (stiff) livers recovered their functionality when placed in a soft environment (as that of a healthy liver). Furthermore, treatments aimed at tricking liver cells into believing they are in a healthy, soft liver improved their function and could potentially contribute to treat cirrhosis.

Dataset Information

Metabolic defects in splenic B cell compartments from patients with liver cirrhosis.

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Metabolic defects in splenic B cell compartments from patients with liver cirrhosis.

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