Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Abstract

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

“…Together, these findings suggest that Mer signaling promotes hepatic fibrosis. Independently, patients with acute liver failure have been found to display markedly elevated numbers of Mer + macrophages and monocytes in their liver, lymph nodes, and circulation (Barcena et al, 2015;Bernsmeier et al, 2015;Triantafyllou et al, 2018), and Mer has, therefore, emerged as a target in the treatment of liver disease (Mukherjee et al, 2016;Bellan et al, 2019).…”

Diverse Macrophage Populations Contribute to the Inflammatory Microenvironment in Premalignant Lesions During Localized Invasion

“…Our cellular identification approach and gene expression analysis suggest that there are six distinct macrophage subpopulations in premalignant PN1a mammary glands. Myeloid clusters 0 and 3 share genes found in macrophages in the normal mammary gland (35,38,39,48), whereas clusters 2, 6, and 8 express genes that have been described in established tumors (37,41,49,50). Cluster 8 decreases substantially in invasive lesions (Figure 2A), indicating that lipid-associated macrophages do not expand during progression to tumors in this model.…”

“…Genes in these pathways are significantly downregulated in cluster 6, which in contrast are enriched for pathways involved in T cell activation, chemotaxis, and MAPK/ERK signaling ( Figure 5B ). Differentially expressed genes include numerous inflammatory chemokines that mediate macrophage recruitment ( Ccl2, Ccl3, Ccl7, Ccl8 ) as well as genes that inhibit inflammation ( Gas6, Ptp1b, Igf ) ( 5 , 46 , 49 ). While numerous pathways, such as T cell activation and proliferation, Leukocyte chemotaxis, and Response to TNF, implicate anti-tumor activity, ERK signaling in macrophages has been shown to be tumor-promoting by exerting both anti-inflammatory and pro-invasive properties ( 51 ).…”

“…Finally, cluster 0 is enriched for pathways involving endocytosis, endosomes, and the ECM ( Figure 5C ), consistent with stromal-associated tissue resident macrophages in the mammary gland ( 35 ). This subpopulation differentially expresses genes that have been shown to be tissue-reparative ( Hmox1, Gas6 ) ( 49 , 52 ) and tumor-promoting ( Pf4, Fgfr1 , and Nrp2 ) ( 53 – 55 ).…”

Differential TAM receptor regulation of hepatic physiology and injury

“…Together, these findings suggest that Mer signaling promotes hepatic fibrosis. Independently, patients with acute liver failure have been found to display markedly elevated numbers of Mer + macrophages and monocytes in their liver, lymph nodes, and circulation (22)(23)(24), and Mer has therefore emerged as a target in the treatment of liver disease (25,26).…”