Abstract
Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.
Highlights
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins such as collagen, resulting from chronic liver inflammation mediated by infectious agents, excessive alcohol abuse, non-alcoholic steatohepatitis (NASH), and autoimmune liver diseases [1]
The frequencies of Foxp3+ Treg cells were significantly increased in the livers of CCl4treated mice, compared with those in the livers of vehicletreated control mice, while the levels of Treg cells in the spleen were comparable between the two groups (Figures 1B,C)
ST2 expression of hepatic Treg cells was higher than splenic Treg cells and after CCl4 injections, the frequencies of ST2+ Treg cells were significantly increased and correlated with protein levels of IL-33, suggesting that Treg expansion may be driven by IL33 released from damaged hepatocytes (Figures 1E–G)
Summary
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins such as collagen, resulting from chronic liver inflammation mediated by infectious agents, excessive alcohol abuse, non-alcoholic steatohepatitis (NASH), and autoimmune liver diseases [1]. It is widely appreciated that various types of inflammatory immune cells mediate chronic tissue inflammation in response to liver injury and the pathogenesis of liver fibrosis. Treg Function in CCl4-Induced Liver Fibrosis abundant inflammatory monocytes and macrophages are recruited to the inflamed liver tissue and are involved in the augmentation of liver fibrosis. Activated innate and adaptive immune cells stimulate hepatic stellate cells to secrete extracellular matrix proteins, resulting in fibrotic changes in the liver that severely impair physiological liver functions. The mechanisms by which fibrotic tissue immune responses in the inflamed liver are negatively regulated remain unknown
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