Abstract
TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.
Highlights
Axl and MerTK seem to play an important role in liver immune homeostasis, by suppressing inflammatory responses and promoting the removal of apoptotic cells
Myeloid-specific deletion of Axl and MerTK leads to liver damage, apoptotic cell accumulation and inflammatory infiltrates in the livers of ageing mice
Sustained pathological Axl and MerTK signaling in non-parenchymal cells play a role in hepatic fibrosis
Summary
TAM receptors are one of the 20 families of receptor tyrosine kinases. They comprise three receptors that share a similar structure: Tyro-3, Axl and MerTK. = Phosphatidylserine, EGF = epidermal growth factor, LG = laminin G, Ig = immunoglobulinlike, FNIII = fibronectin type III, ADAM10/17 = A Disintegrin and metalloproteinase domaincontaining protein 10/17, TM = transmembrane, TKD = tyrosine kinase domain, IFNAR = type I interferon receptor, TLR = toll-like receptor, SOCS1/3 = suppressors of cytokine signaling 1 and 3, STAT = signal transducer and activator of transcription, NF-κB = nuclear factor kappa-light-chainenhancer of activated B cells. The pattern of TAM receptor activation is defined by an initial binding of the ligand LG-like domains to the TAM receptor’s Ig-like domains, which leads to receptor dimerization, with subsequent trans-autophosphorylation of the kinase domains and the activation of intracellular signaling cascades [14,15]
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