BaCKgRoUND aND aIMS: Nonalcoholic steatohepatitis is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear.appRoaCH aND ReSUltS: In this study, we report that NASH livers accumulate B cells with elevated proinflammatory cytokine secretion and antigen-presentation ability. Single-cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro-inflammatory function. Accordingly, B-cell deficiency ameliorated NASH progression, and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B-cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell-specific deletion of MyD88 reduced hepatic T cell-mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cellreceptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH. CoNClUSIoN:Our findings reveal that a gut microbiotadriven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH through innate and adaptive immune mechanisms. (Hepatology 2021;74:704-722). NAFLD is estimated to affect 30% of the population and is now recognized as the most prevalent chronic liver disease worldwide. (1) The disease covers a wide spectrum of liver pathology, ranging from simple lipid accumulation to the development of NASH, defined by hepatic steatosis, local inflammation, hepatocellular injury, and fibrosis. (2) NASH-associated inflammation is driven by innate and adaptive immune mechanisms comprising macrophages, dendritic cells, neutrophils, and lymphocytes. (3) Recent single-cell transcriptome analyses have uncovered the heterogeneity of intrahepatic
Rationale: The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages (mψs) in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac-resident immune cells influence the early phase of hypertrophy development has not been established. Objective: To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload-induced by transverse aortic constriction (TAC). Methods and Results: We performed cytometry-by-time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac mψs 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and mψs, categorized as either resident or recruited mψs, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac-resident mψs early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited mψs by monocytes before performing TAC. This preferential depletion of resident mψs resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Mψ-depletion in CCR2 knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived mψs. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells. Conclusions: Cardiac resident mψs are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.
Objective Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH). Notably, immune cell-driven inflammation is a key mechanism in the transition from fatty liver to the more serious NASH. Although exercise training is effective in ameliorating obesity-related diseases, the underlying mechanisms of the beneficial effects of exercise remain unclear. It is unknown whether there is an optimal modality and intensity of exercise to treat NAFLD. The objective of this study was to determine whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MIT) is more effective at ameliorating the progression of NASH. Methods Wild-type mice were fed a high-fat, high-carbohydrate (HFHC) diet for 6 weeks and left sedentary (SED) or assigned to either an MIT or HIIT regimen using treadmill running for an additional 16 weeks. MIT and HIIT groups were pair-fed to ensure that energy intake was similar between the exercise cohorts. To determine changes in whole-body metabolism, we performed insulin and glucose tolerance tests, indirect calorimetry, and magnetic resonance imaging. NASH progression was determined by triglyceride accumulation, expression of inflammatory genes, and histological assessment of fibrosis. Immune cell populations in the liver were characterized by cytometry by time-of-flight mass spectrometry, and progenitor populations within the bone marrow were assessed by flow cytometry. Finally, we analyzed the transcriptional profile of the liver by bulk RNA sequencing. Results Compared with SED mice, both HIIT and MIT suppressed weight gain, improved whole-body metabolic parameters, and ameliorated the progression of NASH by reducing hepatic triglyceride levels, inflammation, and fibrosis. However, HIIT was superior to MIT at reducing adiposity, improving whole-body glucose tolerance, and ameliorating liver steatosis, inflammation, and fibrosis, without any changes in body weight. Improved NASH progression in HIIT mice was accompanied by a substantial decrease in the frequency of pro-inflammatory infiltrating, monocyte-derived macrophages in the liver and reduced myeloid progenitor populations in the bone marrow. Notably, an acute bout of MIT or HIIT exercise had no effect on the intrahepatic and splenic immune cell populations. In addition, bulk mRNA sequencing of the entire liver tissue showed a pattern of gene expression confirming that HIIT was more effective than MIT in improving liver inflammation and lipid biosynthesis. Conclusions Our data suggest that exercise lessens hepatic inflammation during NASH by reducing the accumulation of hepatic monocyte-derived inflammatory macrophages and bone marrow precursor cells. Our findings also indicate that HIIT is superior to MIT in ameliorating the disease in a dietary mouse model of NASH.
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