*3.7. TGF-*β*1*

It has been stressed before that one of the main drivers of fibrosis is TGF-β1, which is strongly upregulated in the process of fibrosis and leads to activation and ECM production by HSCs and portal

fibroblasts [166]. In addition to liver resident cells, e.g., HSCs and Kupffer cells, MCs also express and secrete TGF-β1 to promote fibrosis (see above). The pro-fibrogenic master cytokine, TGF-β1, regulates the expression of proteases and their release [167]. In contrast, MC-specific receptors controlling cellular degranulation, including KIT (ligand SCF) and FcεRI (ligand IgE), are down-regulated in vitro and in vivo by TGF-β1 in a SMAD-dependent fashion [168]. In addition, TGF-β1 suppresses IL-33-induced cytokine production and MC activation by interfering with MAP kinase phosphorylation [169]. Aside from the expression and liberation of effectors, a broad spectrum of MC functions is modulated by TGF-β1, including proliferation, cell cycle control, and apoptosis [170]. Another vital function of MC biology modulated by TGF-β is migration/chemotaxis. Interestingly, chemotaxis is not mediated by the classical SMAD pathway, but by MEK1/2 signaling [171]. Moreover, the SRC family kinase FYN plays a critical role in TGF-β1-mediated MC migration in vitro and in vivo [172]. Those observations show that in the environment of fibrosis MCs may contribute to the progression of the disease by releasing TGF-β1, affecting HSCs and portal fibroblasts. In turn, MCs also express TGF-β receptors and are targets for this ligand [107]. Nevertheless, the effects are somewhat counterbalanced, leading on one hand to chemotaxis and increased effector synthesis [107,173], and on the other hand apoptosis, blocking late stage maturation and sensor suppression [173–175]. Therefore, the TGF-β1 response in MCs is a double-edged sword, which largely depends on the molecular context.

In summary, there are many mediators released by activated MCs that contribute to liver disease by directly interfering with the recruitment and activation of inflammatory blood cells, stimulating proliferation of pro-fibrogenic cells, promoting ECM synthesis, or inhibiting its degradation (Figure 3).

**Figure 3.** Schematic overview of known functional interactions between mast cells and liver cells in hepatic fibrogenesis. Mast cells (MCs) activation and degranulation leads to a production/release of many biological active compounds including TGF-β1, tryptase, chymase, histamine, TNF-α, and human leukocyte antigen G (HLA-G). These soluble mediators trigger the recruitment/activation of

inflammatory blood cells and synthesis of an extracellular matrix (ECM) by stimulating the propagation of pro-fibrogenic cells (hepatic stellate cells, portal myofibroblasts) and inhibiting its ECM degradation. Furthermore, the compounds lead to the activation of liver-resident Kupffer cells and cholangiocyte proliferation. It is further discussed that MCs modulate parenchymal cell proliferation and biological features of endothelial cells. In addition, the cargos present in extracellular vesicles (EV) that are released from MCs into the extracellular milieu facilitate pro-fibrogenic signaling pathways in recipient cells. Abbreviations used are: α-SMA, α-smooth muscle actin; Col I, collagen type I; HLA-G, human leukocyte antigen G; HR, histamine receptor; HSC, hepatic stellate cell; IL-22, interleukin 22; MCP-1, monocyte chemoattractant protein-1; MFB, myofibroblast; PAR-2, Protease-activator receptor-2; PSC, primary sclerosing cholangitis; SCF, stem cell factor; SYP-9, synaptophysin-9; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α.
