Liver Fibrosis Occurs Through Dysregulation of MyD88-Dependent Innate B-Cell Activity
Open accessAbstract
Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride–treated, B cell–deficient µMT mice, showing that B cells are required. The retinoic acid produced by HSCs augmented B‐cell survival, plasma cell marker CD138 expression, and immunoglobulin G production. These activities were reversed following addition of the retinoic acid inhibitor LE540. Transcriptional profiling of fibrotic liver B cells revealed increased expression of genes related to activation of nuclear factor κ light chain enhancer of activated B cells, proinflammatory cytokine production, and CD40 signaling, suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expression), constitutive immunoglobulin G production, and secretion of the proinflammatory cytokines tumor necrosis factor‐α, monocyte chemoattractant protein‐1, and macrophage inflammatory protein‐1α. Likewise, targeted deletion of B‐cell‐intrinsic myeloid differentiation primary response gene 88 signaling, an innate adaptor with involvement in retinoic acid signaling, resulted in reduced infiltration of migratory CD11c + dendritic cells and Ly6C ++ monocytes and, hence, reduced liver pathology. Conclusion : Liver fibrosis occurs through a mechanism of HSC‐mediated augmentation of innate B‐cell activity. These findings highlight B cells as important “first responders” of the intrahepatic immune environment. (H epatology 2015;61:2067‐2079)
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Retinoic acid signaling by HSCs promotes B cell survival and activation while B cells secrete inflammatory cytokines.
“Retinoic acid (RA) signaling by HSCs promotes B cell survival and activation while, in turn, B cells secrete inflammatory cytokines (66).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [66]
B cells directly contribute to the evolution of inflammation and fibrosis in mouse models of NASH and hepatotoxicity.
“Consistently, B cells have been shown to directly contribute to the evolution of inflammation and fibrosis in mouse models of NASH and hepatotoxicity.”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
The profibrotic role of B cells during CCl4-induced liver injury depends on the adaptor protein MYD88.
“The profibrotic role of B cells during CCl4‐induced liver injury depends on the adaptor protein, myeloid differentiation primary response 88 (MYD88), which is indispensable for innate immunity and involved in the retinoid acid signaling pathway.( 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
B cells promote hepatic fibrosis in the CCl4-induced mouse model of hepatotoxicity.
“B cells also seem to promote hepatic fibrosis in the CCl4‐induced mouse model of hepatotoxicity.( 59 , 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
HSC-derived retinoid acid induces B-cell survival and innate-like proinflammatory function in a feed-forward mechanism that drives liver fibrosis.
“In turn, HSC‐derived retinoid acid induces B‐cell survival and innate‐like proinflammatory function in a feed‐forward mechanism that drives liver fibrosis.( 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
B-cell-deficient mice treated with CCl4 have substantially attenuated liver fibrosis with reduced collagen deposition, infiltration of immune cells, and HSC activation, suggesting that B cells are required for liver fibrogenesis.
“B‐cell–deficient mice treated with CCl4 have substantially attenuated liver fibrosis with reduced collagen deposition, infiltration of immune cells, and HSC activation, suggesting that B cells are required for liver fibrogenesis.( 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
Genetic ablation of B cells results in suppressed fibrosis in CCl4-treated mice.
“Intrahepatic B cells from CCl4‐treated fibrotic mice show increased activation and production of proinflammatory cytokines whereas their genetic ablation results in suppressed fibrosis.( 59 , 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
Intrahepatic B cells from CCl4-treated fibrotic mice show increased activation and production of proinflammatory cytokines.
“Intrahepatic B cells from CCl4‐treated fibrotic mice show increased activation and production of proinflammatory cytokines whereas their genetic ablation results in suppressed fibrosis.( 59 , 60 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [60]
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- Authors
- Thapa, M., Chinnadurai, R., Velazquez, V. M., Tedesco, D., Elrod, E., Han, J., Sharma, P., Ibegbu, C., Gewirtz, A., Anania, F., Pulendran, B., Suthar, M. S., & Grakoui, A.
- Affiliations
- Emory University (US)
- Georgia State University (US)
- Corresponding author
- Grakoui, Arash
- ORCID
- Venue
- Hepatology
- Published
- 2015-03-25
- Volume
- 61
- Issue
- 6
- Pages
- 2067-2079
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4441566
- OpenAlex
- W1909034893
- Cited by
- 101
- References
- 35
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 8 · 2022: 15 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 3 · 2015: 3
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AI070101, DK083356)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver fibrosis, hepatic stellate cells, B cells, MyD88 signaling, retinoic acid signaling, NF-κB, CD40 signaling, inflammatory cytokines, dendritic cells, monocytes, chronic liver disease, carbon tetrachloride, IgG
- MeSH terms
- Animals, B-Lymphocytes, Cell Differentiation, Liver Cirrhosis, Male, Mice, Inbred C57BL, Tretinoin, Mice, Knockout, Gene Expression Profiling, Myeloid Differentiation Factor 88, Hepatic Stellate Cells
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