Microbiota‐Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling

Abstract

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

Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH

“…Splenic, BM, and blood immune cells were isolated, as previously described [ 21 ]. For cytometry by time-of-flight mass spectrometry (CyTOF), cells were stained with 0.5 μg of metal-conjugated primary antibodies (Fluidigm) for 30 min at 4 °C [ 24 ]. Data were collected on a CyTOF 2 instrument (DVS Sciences) and analyzed using Cytobank.…”

Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet

“…As this occurs, the Kupffer cell pool is depleted and recruited monocytes to fill the niche, but these monocyte-derived replacements are more inflammatory than Kupffer cells 25,26 . B cells are also recruited to the liver, where they drive inflammation and fibrogenesis 27 . Multiple studies have demonstrated that preventing this recruitment of additional immune cells or removal of Kupffer cells slows the progression of NAFLD, indicating that immune cell infiltration is a key step in disease progression [27][28][29][30][31] .…”

“…B cells are also recruited to the liver, where they drive inflammation and fibrogenesis 27 . Multiple studies have demonstrated that preventing this recruitment of additional immune cells or removal of Kupffer cells slows the progression of NAFLD, indicating that immune cell infiltration is a key step in disease progression [27][28][29][30][31] .…”

The Emerging Role of B Cells in the Pathogenesis of NAFLD

“…(56) Using sc-RNAseq with superloading and multiplexing, we were able to identify three distinct clusters of B cells, including a predominant mature B-cell population as well as two less-abundant subsets of immature and metabolically active cells enriched with mitochondrial genes. (55) Supporting a fibrogenic function of B cells, sc-RNAseq and ligand-receptor network analysis of NASH livers shows that activated HSCs express increased C-X-C motif chemokine ligand 12 with C-X-C motif chemokine receptor 4 (Cxcr4) in B cells as the potential target. (57) Mature and plasma B-cell clusters have been also detected by sc-RNAseq within areas of scarring in fibrotic livers of patients with cirrhosis.…”