The tyrosine kinase receptors of the TAM family—Tyro3, Axl and Mer—and their main ligand Gas6 (growth arrest-specific 6) have been implicated in several human diseases, having a particularly important role in the regulation of innate immunity and inflammatory response. The Gas6/TAM system is involved in the recognition of apoptotic debris by immune cells and this mechanism has been exploited by viruses for cell entry and infection. Coronavirus disease 2019 (COVID-19) is a multi-systemic disease, but the lungs are particularly affected during the acute phase and some patients may suffer persistent lung damage. Among the manifestations of the disease, fibrotic abnormalities have been observed among the survivors of COVID-19. The mechanisms of COVID-related fibrosis remain elusive, even though some parallels may be drawn with other fibrotic diseases, such as idiopathic pulmonary fibrosis. Due to the still limited number of scientific studies addressing this question, in this review we aimed to integrate the current knowledge of the Gas6/TAM axis with the pathophysiological mechanisms underlying COVID-19, with emphasis on the development of a fibrotic phenotype.

Background and Objectives: TAM receptors—Tyro3, Axl, and Mer—and their ligand Growth Arrest-Specific 6 (Gas6) represent a pleiotropic system implicated in fibrosis. Increased Gas6 and Axl expression have previously been observed in lung samples and fibroblast cultures from Idiopathic Pulmonary Fibrosis (IPF) patients. The study explored the contribution of Gas6/TAM system in fibrosis development and the impact of its pharmacological inhibition in fibroblasts. Materials and Methods: IPF fibroblasts (IPF FBs) and control human pulmonary fibroblasts (HPFs) were treated with R428 (Axl-specific inhibitor), LDC1267 (TAM inhibitor), or Nintedanib (an IPF-approved drug) to evaluate the influence of these drugs on cell proliferation, migration, and the expression of pro-inflammatory and pro-fibrotic genes. Fibroblast-to-myofibroblast differentiation was induced by TGF-β. The impact of IPF FBs and HPF on macrophage polarization was investigated through a co-culture of fibroblasts with monocyte-derived macrophages, with the further gene expression analysis of markers of the M1 (pro-inflammatory) or M2 (pro-fibrotic) polarization forms. Results: Cell proliferation was monitored in fibroblasts treated with TGF-β, the drugs, and their combination. In the presence of LDC1267 and Nintedanib, minor differences in cell confluence were detected between IPF FBs and HPFs; R428 (1 μM) seemed to have a higher inhibitory impact on IPF FBs. Regarding cell migration, the fibroblasts treated with LDC1267 exhibited slower wound closure. R428 treatment led to a relative wound closure of 76% in HPFs but only 56% in IPF FBs (60 h). R428 (1 μM) significantly reduced the expression of the pro-fibrotic markers ACTA2, COL1A1, and FN1 in HPFs and IPF FBs compared to TGF-β treatment. HPFs and IPF FBs co-cultured with monocyte-derived macrophages demonstrated a significantly increased expression of MRC1 while the expression of FN1, TNFα, and CXCL10 was moderately increased. Conclusions: These findings suggest that R428 and LDC1267 modulate the proliferation, migration, and gene expression of activated fibroblasts via TAM signaling. Fibroblast-mediated effects on macrophage polarization underscore the relevance of intercellular crosstalk in fibrotic disease.