Regulation of Progression and Resolution of Liver Fibrosis by Immune Cells

Abstract

The excessive accumulation of extracellular matrix proteins results in fibrosis—a condition implicated in several diseased conditions, such as non-alcoholic steatohepatitis, viral hepatitis, and autoimmune hepatitis. Despite its prevalence, direct and effective treatments for fibrosis are lacking, warranting the development of better therapeutic strategies. Accumulating evidence has shown that liver fibrosis—a condition previously considered irreversible—is reversible in specific conditions. Immune cells residing in or infiltrating the liver, e.g., macrophages, are crucial in the pathogenesis of fibrosis. Given this background, the roles and action mechanisms of various immune cells and their subsets in the progression and recovery of liver fibrosis, particularly concerning non-alcoholic steatohepatitis, are discussed in this review. Furthermore, the development of better therapeutic strategies based on stage-specific properties and using advanced techniques as well as the mechanisms underlying recovery are elaborated. In conclusion, we consider the review comprehensively provides the present achievements and future possibilities revolving around fibrosis treatment.

Therapeutic modulation of the liver immune microenvironment

“…Although the latter approach has shown some beneficial effects in smaller trials involving patients with decompensated cirrhosis and acute-on-chronic liver failure, granulocyte colony-stimulating factor had no significant beneficial effect on patients with acute-on-chronic liver failure in a large multicenter randomized controlled European trial. [199] As macrophages, particularly their "repair" or alternatively activated phenotypes, are essential for the resolution of inflammation and proper tissue regeneration, [200,201] the adoptive transfer of "programmed" macrophages has emerged as an attractive strategy. In the mouse liver fibrosis model of repetitive carbon tetrachloride injections, the transfer of immature bone marrow monocytes aggravated liver fibrosis, whereas the transfer of (ex vivo) properly differentiated macrophages ameliorated hepatic fibrosis.…”

“…As macrophages, particularly their “repair” or alternatively activated phenotypes, are essential for the resolution of inflammation and proper tissue regeneration, 200,201 the adoptive transfer of “programmed” macrophages has emerged as an attractive strategy. In the mouse liver fibrosis model of repetitive carbon tetrachloride injections, the transfer of immature bone marrow monocytes aggravated liver fibrosis, whereas the transfer of ( ex vivo ) properly differentiated macrophages ameliorated hepatic fibrosis 202,203 .…”

Ambiguous Pathogenic Roles of Macrophages in Alcohol-Associated Liver Diseases

“…The mechanisms of macrophage polarization in advanced stages of fibrosis and cirrhosis are thought to be mediated by various signaling pathways, including those activated by pro-inflammatory chemokines such as IFN-γ and TNF-α, as well as anti-inflammatory cytokines including IL-4 and IL-13. 52 …”

“…The mechanisms of macrophage polarization in advanced stages of fibrosis and cirrhosis are thought to be mediated by various signaling pathways, including those activated by pro-inflammatory chemokines such as IFN-γ and TNF-α, as well as anti-inflammatory cytokines including IL-4 and IL-13. 52 Additionally, patients with cirrhosis often experience complications, such as infections, leading to high morbidity and mortality. Indeed, more than 30% of patients with advanced cirrhosis develop bacterial infections.…”