Table 1 Study on the mechanism of TAM receptor in various lung diseases
Diseases | TAM receptors | Study type | Subjects | Signal pathway | Main findings | Ref |
|---|---|---|---|---|---|---|
lung inflammation | AXL | In vivo  +  In vitro | Rat alveolar epithelial MLE-12 cells | Gas6/Axl/SOCS3 | Gas6/Axl signalling activates SOCS3-mediated pathways and attenuates IR-associated inflammation and injury | [74] |
In vivo  +  In vitro | C57BL/6 J mice, Mouse primary alveolar microparticles, Human T lymphocytes, PBMCs | ROS/ADAM10/AXL | DEX promotes macrophage proliferation through the ROS/ADAM10/AXL signalling pathway, thereby effectively attenuating septic lung injury | [78] | ||
In vivo  +  In vitro | Male C57BL/6 wild-type (WT) mice, Axl−/−mice, MerTk−/− mice, Colonic macrophage isolation (cMPs), pMPs | – | MerTk and Axl specifically coordinate the clearance of apoptotic cells in different environments and play important roles in lung immune homeostasis, silicosis cell burial and inflammation regulation | [75] | ||
MERTK | ||||||
In vivo  +  In vitro | C57BL/MerTK−/−mice, B6.129 mice, primary alveolar microparticles | – | The resident alveolar macrophages effectively remove the microparticles released from lung injury through MerTK mediated phagocytosis | [76] | ||
In vivo  +  In vitro | C57BL/6 J mice, Mertk−/− mice, human endothelial cells | MERTK/VE—cadherin, MERTK/PECAM—1, MERTK/Rac1 | The absence of MERTK in human pulmonary microvascular endothelial cells and all cells in vivo aggravated the inflammatory response. However, selective MERTK depletion of endothelial cells in vivo cannot replicate this response | [77] | ||
lung fibrosis | AXL | In vitro | Multi-potent cells | – | Axl is activated during the proliferation of epithelial cells in idiopathic pulmonary fibrosis, and the integrity of the epithelial barrier is lost | [102] |
In vitro  +  In vivo | ATII cells treated with BLM, C57BL / 6 Gas6−/− mice treated with BLM | Gas6/AXL | Mouse recombinant Gas6 (rGas6) attenuates pulmonary fibrosis by inhibiting the EMT process and apoptosis of ATII and fibroblast activation | [103] | ||
In vivo  +  In vitro | SCID/Bg mice, Gas6−/−mice, primary lung fibroblasts | Gas6/TAM/ RTK pathway | Gas6 / TAM receptor activity is involved in the activation of lung fibroblasts in IPF. Targeting the RTK signalling pathway may be an effective anti-fibrosis strategy for the treatment of IPF | [11] | ||
MERTK | Human body | IPF lung tissue | SPP1/MERTK | Macrophages expressing SPP 1 / MERTK proliferate and promote the activation of IPF myofibroblasts and pulmonary fibrosis | [12] | |
In vitro  +  In vivo | lung macrophages, BLM-induced pulmonary fibrosis mouse model | – | Macrophages overexpressing MERTK have pro-fibrotic functions and eliminate pro-fibrotic effects by down-regulating MERTK through endocytosis | [104] | ||
TYRO3 | In vitro  +  In vivo | SCID / Bg mice, Gas6−/−mice, Primary lung fibroblasts | Gas6/TAM/ RTK pathway | Mediating the pro-fibrotic effects of Gas6 as a means of activating the Gas6/TAM receptor pathway to promote pulmonary fibrosis | [11] | |
lung cancer | AXL | In vitro | SCLC and NSCLC cell lines | – | Axl was co-expressed with Gas6 and was expressed in NSCLC cell line but not in SCLC cell line. The histotypic and phenotypic expression of Axl determines the direction of differentiation of lung cancer cells | [117] |
In vitro | CL1 subline | – | Ectopic overexpression of AXL may lead to enhanced invasiveness and increased drug resistance of lung cancer cells | [17] | ||
In vitro | NSCLC cell lines with low metastatic (CL1-0) and high metastatic (CL1-5) potentials | Akt1/Rac1 | Oxidative stress enhances Axl-mediated cell migration and invasion through an Akt1 / Rac1-dependent mechanism | [15] | ||
In vitro  +  In vivo | A549, H1299, H838 and H1975 cell lines, mouse xenograft model | AXL/MET | PFKP binds to AXL to activate the AXL signalling pathway and promotes MET phosphorylation to promote NSCLC progression. Nanoparticles-mediated PFKP silencing reduces cell proliferation, migration, invasion, and colony formation by inhibiting the AXL-MET axis | [129] | ||
In vitro  +  In vivo | CD73-silenced stable cell lines, overexpression CD73 cell lines, nude mouse models | CD73 / AXL | CD73 may activate AXL by directly binding to the R55 site of the AXL extracellular region without relying on GAS6 and promote NSCLC metastasis and invasion by regulating epithelial-mesenchymal transition (EMT) through the CD73 / AXL axis | [120] | ||
In vitro | Tumor samples from NSCLC patients treated with ICI monotherapy | – | AXL expression is associated with aggressive phenotypic traits, and its upregulation and hypermutation regulate the tumor microenvironment, so AXL inhibitors in combination with current chemo-immunotherapeutic regimens could benefit NSCLC patients | [138] | ||
In vitro | H1299-parental cells, cancer stem cells of human NSCLC cell line H1299 (H1299-sdCSCs) | AXL/ALDH/SLUG | EGCG Inhibits Stemness and Tumorigenicity of Human Lung Cancer Cells by Suppressing AXL | [130] | ||
In vitro  +  In vivo | BMDM BALB/c mice | – | Targeting and inhibiting AXL can help tumor-associated macrophages polarize to the M1 phenotype and activate the anti-tumor immunity of macrophages, which can effectively interfere with M2 polarization and its tumor-promoting activity. | [132] | ||
In vivo  +  In vitro | Subcutaneous transplantation of NSCLC, in vitro cloning of NSCLC in nude mice | – | Both MERTK and Axl have complementary and overlapping roles in NSCLC, and MERTK or AXL favours tumor cell survival by inhibiting NSCLC cell apoptosis, promoting their growth, and reducing chemosensitivity | [56] | ||
MERTK | ||||||
In vitro | NIH 3T3 cells | – | CSF-1 treatment induced MERTK autophosphorylation, transformed NIH 3T3 cells, and induced lung tumorigenesis | [153] | ||
In vitro | Human BL-41 lymphoma cells | – | Autooxidation and oligomerization of the apoptotic cell surface protein S are required for Mer tyrosine kinase mediated phagocytosis of apoptotic cells | [150] | ||
TYRO3 | In vitro | NSCLC cell line, SCLC cell line, normal bronchial epithelial cells | – | Co-expression of TYRO3, and anticoagulant protein S, TYRO3 participates in the development or progression of lung cancer by affecting local anticoagulation by binding with anticoagulant protein S or local proliferation or differentiation process | [19] | |
COVID-19 | AXL | In vitro | H1299 cell, BEAS-2B cell | – | AXL is a candidate receptor for SARS-CoV-2 that can mediate viral entry into cells and can promote infection of lung and bronchial epithelial cells | [20] |
Human body | COVID-19 Patient plasma samples | – | Plasma levels of Gas6 and sAXL were associated with COVID-19 severity, which gradually increased with increasing disease severity | [171] | ||
Human body | COVID-19 Patient plasma samples | – | Serum ACE2 and AXL Levels Correlate with COVID-19 Severity | [167] | ||
MERTK | Human body | COVID-19 Patient serum samples | – | Elevated Concentrations of Galactaglutinin-3, a Ligand Associated with MERTK and TYRO3 Activation, Promote Fibrosis and Positively Correlate with Markers of Inflammation and Tissue Damage | [170] | |
TYRO3 | ||||||
TAM receptor | In vivo | Pros1+/− heterozygous mice, Pros1−/− mice | – | Depletion of PROS1 in the blood, which leads to dysfunctional coagulation and allows blood vessels to rupture and bleed due to necrosis, may also reduce TAM ligand levels | ||
In vivo | A mouse model of thrombosis | Gas6/TAM | Gas6 enhances platelet degranulation and aggregation through TAM, promotes platelet activation and mediates thrombosis, thereby preventing thrombosis, preventing vascular injury, and repairing endothelium without increasing bleeding | [39] | ||
In vivo  +  In vitro | Mice deficient in Gas6, Tyro3, Axl or Mer, wild-type (WT) mice, platelets | Gas6/TAM | ADP-P2Y (12) and Gas6 synergistically activate PI3K and induce TAM receptor signalling to achieve sustained activation of aIIbb3 and thrombus stability | [38] |