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http://dx.doi.org/10.14348/molcells.2018.0419

Anti-Inflammatory Role of TAM Family of Receptor Tyrosine Kinases Via Modulating Macrophage Function  

Lee, Chang-Hee (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University)
Chun, Taehoon (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University)
Publication Information
Molecules and Cells / v.42, no.1, 2019 , pp. 1-7 More about this Journal
Abstract
Macrophage is an important innate immune cell that not only initiates inflammatory responses, but also functions in tissue repair and anti-inflammatory responses. Regulating macrophage activity is thus critical to maintain immune homeostasis. Tyro3, Axl, and Mer are integral membrane proteins that constitute TAM family of receptor tyrosine kinases (RTKs). Growing evidence indicates that TAM family receptors play an important role in anti-inflammatory responses through modulating the function of macrophages. First, macrophages can recognize apoptotic bodies through interaction between TAM family receptors expressed on macrophages and their ligands attached to apoptotic bodies. Without TAM signaling, macrophages cannot clear up apoptotic cells, leading to broad inflammation due to over-activation of immune cells. Second, TAM signaling can prevent chronic activation of macrophages by attenuating inflammatory pathways through particular pattern recognition receptors and cytokine receptors. Third, TAM signaling can induce autophagy which is an important mechanism to inhibit NLRP3 inflammasome activation in macrophages. Fourth, TAM signaling can inhibit polarization of M1 macrophages. In this review, we will focus on mechanisms involved in how TAM family of RTKs can modulate function of macrophage associated with anti-inflammatory responses described above. We will also discuss several human diseases related to TAM signaling and potential therapeutic strategies of targeting TAM signaling.
Keywords
anti-inflammatory response; cell signaling; innate immunity; macrophage; TAM family of receptor tyrosine kinase;
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1 Ben-Batalla, I., Schultze, A., Wroblewski, M., Erdmann, R., Heuser, M., Waizenegger, J.S., Riecken, K., Binder, M., Schewe, D., Sawall, S., et al. (2013). Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 122, 2443-2452.   DOI
2 Caberoy, N.B., Alvarado, G., Bigcas, J.L., and Li, W. (2012). Galectin-3 is a new MerTK-specific eat-me signal. J. Cell Physiol. 227, 401-407.   DOI
3 Caberoy, N.B., Zhou, Y., and Li, W. (2010). Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J. 29, 3898-3910.   DOI
4 Camenisch, T.D., Koller, B.H., Earp, H.S., and Matsushima, G.K. (1999). A novel receptor tyrosine kinase, Mer, inhibits TNF-${\alpha}$ production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162, 3498-3503.
5 Caraux, A., Lu, Q., Fernandez, N., Riou, S., Di Santo, J.P., Raulet, D.H., and Roth, C. (2006). Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat. Immunol. 7, 747-754.   DOI
6 Carrera Silva, E.A., Chan, P.Y., Joannas, L., Errasti, A.E., Gagliani, N., Bosurgi, L., Jabbour, M., Perry, A., Smith-Chakmakova, F., Mucida, D., et al. (2013). T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39, 160-170.   DOI
7 Castellano, F., Montcourrier, P., and Chavrier, P. (2000). Membrane recruitment of Rac1 triggers phagocytosis. J. Cell Sci. 113, 2955-2961.   DOI
8 Fourgeaud, L., Traves, P.G., Tufail, Y., Leal-Bailey, H., Lew, E.D., Burrola, P.G., Callaway, P., Zagorska, A., Rothlin, C.V., Nimmerjahn, A., et al. (2016). TAM receptors regulate multiple features of microglial physiology. Nature 532, 240-244.   DOI
9 Nakahira, K., Haspel, J.A., Rathinam, V.A., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., and Kim, H.P. (2011). Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230.   DOI
10 O'Bryan, J.P., Frye, R.A., Cogswell, P.C., Neubauer, A., Kitch, B., Prokop, C., Espinosa, R., Beau, M.M.L., Earp, H.S., and Liu, E.T. (1991). Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol. Cell Biol. 11, 5016-5031.   DOI
11 Paolino, M., Choidas, A., Wallner, S., Pranjic, B., Uribesalgo, I., Loeser, S., Jamieson, A.M., Langdon, W.Y., Ikeda, F., Fededa, J.P., et al. (2014). The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508-512.   DOI
12 Prasad, D., Rothlin, C.V., Burrola, P., Burstyn-Cohen, T., Lu, Q., de Frutos, P.G., and Lemke, G. (2006). TAM receptor function in the retinal pigment epithelium. Mol. Cell Neurosci. 33, 96-108.   DOI
13 Robinson, D.R., Wu, Y.M., and Lin, S.F. (2000). The protein tyrosine kinase family of the human genome. Oncogene 19, 5548-5557.   DOI
14 Rothlin, C.V., Carrera-Silva, E.A., Bosurgi, L., and Ghosh, S. (2015). TAM receptor signaling in immune homeostasis. Annu. Rev. Immunol. 33, 355-391.   DOI
15 Rothlin, C.V., Ghosh, S., Zuniga, E.I., Oldstone, M.B., and Lemke, G. (2007). TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124-1136.   DOI
16 Sheridan, C. (2013). First Axl inhibitor enters clinical trials. Nat. Biotechnol. 31, 775-756.   DOI
17 Gruber, R.C., Ray, A.K., Johndrow, C.T., Guzik, H., Burek, D., de Frutos, P.G., and Shafit-Zagardo, B. (2014). Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis. J. Neurosci. 34, 16320-16335.   DOI
18 Gjerdrum, C., Tiron, C., Hoiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B.T., et al. (2010). Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc. Natl. Acad. Sci. USA 107, 1124-1129.   DOI
19 Graham, D.K., Dawson, T.L., Mullaney, D.L., Snodgrass, H.R., and Earp, H.S. (1994). Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ. 5, 647-657.
20 Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140, 883-899.   DOI
21 Hafizi, S., and Dahlback, B. (2006). Gas6 and protein S. Vitamin Kdependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J. 273, 5231-5244.   DOI
22 Sasaki, T., Knyazev, P.G., Clout, N.J., Cheburkin, Y., Gohring, W., Ullrich, A., Timpl, R., and Hohenester, E. (2006). Structural basis for Gas6-Axl signalling. EMBO J. 25, 80-87.   DOI
23 Han, J., Bae, J., Choi, C.Y., Choi, S.P., Kang, H.S., Jo, E.K., and Lee, M.S. (2016). Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. Autophagy 12, 2326-2343.   DOI
24 Hirschi, K.M., Chapman, S., Hall, P., Ostergar, A., Winden, D.R., Reynolds, P.R., and Arroyo, J.A. (2018). Gas6 protein induces invasion and reduces inflammatory cytokines in oral squamous cell carcinoma. J. Oral. Pathol. Med. 47, 748-754.   DOI
25 Huang, M., Rigby, A.C., Morelli, X., Grant, M.A., Huang, G., Furie, B., and Furie, B.C. (2003). Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat. Struct. Biol. 10, 751-756.   DOI
26 Jung, M. (2004). Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy. Eur. J. Immunol. 34, 481-493.   DOI
27 Klionsky, D.J., and Emr, S.D. (2000). Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721.   DOI
28 Shibata, T., Ismailoglu, U.B., Kittan, N.A., Moreira, A.P., Coelho, A.L., Chupp, G.L., Kunkel, S.L., Lukacs, N.W., Hogaboam, C.M. (2014). Role of growth arrest-specific gene 6 in the development of fungal allergic airway disease in mice. Am. J. Respir. Cell Mol. Biol. 51, 615-625.   DOI
29 Smiley, S.T., Stitt, T.N., and Grusby, M.J. (1997). Cross-linking of protein S bound to lymphocytes promotes aggregation and inhibits proliferation. Cell Immunol. 181,120-126.   DOI
30 Schroder, K., and Tschopp, J. (2010). The inflammasomes. Cell 140, 821-832.   DOI
31 Scott, R.S. (2001). Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207-211.   DOI
32 Lemke, G., and Burstyn-Cohen, T. (2010). TAM receptors and the clearance of apoptotic cells. Ann. NY Acad. Sci. 1209, 23-29.   DOI
33 Segawa, K. (2014). Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164-1168.   DOI
34 Lai, C., Gore, M., and Lemke, G. (1994). Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene 9, 2567-2578.
35 Lawrence, T., and Natoli, G. (2011). Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750-761.   DOI
36 Lew, E.D., Oh, J., Burrola, P.G., Lax, I., Zagorska, A., Traves, P.G., Schlessinger, J., and Lemke, G. (2014). Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. Elife, 3, e03385.   DOI
37 Lewis, C.E., and Pollard, J.W. (2006). Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605-612.   DOI
38 Linger, R.M., Cohen, R.A., Cummings, C.T., Sather, S., Migdall-Wilson, J., Middleton, D.H., Lu, X., Baron, A.E., Franklin W.A., Merrick, D.T., et al. (2013). Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene 32, 3420-3431.   DOI
39 Linger, R.M., Keating, A.K., Earp, H.S., and Graham, D.K. (2008). TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 100, 35-83.   DOI
40 Lingnau, M., Hoflich, C., Volk, H.D., Sabat, R., and Docke, W.D. (2007). Interleukin-10 enhances the CD14-dependent phagocytosis of bacteria and apoptotic cells by human monocytes. Hum. Immunol. 68, 730-738.   DOI
41 Sosic, D., Richardson, J.A., Yu, K., Ornitz, D.M., and Olson, E.N. (2003). Twist regulates cytokine gene expression through a negative feedback loop that represses $NF-{\kappa}B$ activity. Cell 112, 169-180.   DOI
42 Sharif, M. N., Sosic, D., Rothlin, C.V., Kelly, E., Lemke, G., Olson, E.N., and Ivashkiv, L.B. (2006). Twist mediates suppression of inflammation by type I IFNs and Axl. J. Exp. Med. 203, 1891-1901.   DOI
43 Sica, A., and Bronte, V. (2007). Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 117, 1155-1166.   DOI
44 Solinas, G., Germano, G., Mantovani, A., and Allavena P. (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol. 86, 1065-1073.   DOI
45 Stitt, T.N. (1995). The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 80, 661-670.   DOI
46 Medzhitov, R. (2009). Approaching the asymptote: 20 years later. Immunity 30, 766-775.   DOI
47 Loges, S., Schmidt, T., Tjwa, M., Van Geyte, K., Lievens, D., Lutgens, E., and Luttun, A. (2010). Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood 115, 2264-2273.   DOI
48 Lu, Q., and Lemke, G. (2001). Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293, 306-311.   DOI
49 Lu, Q., Gore, M., Zhang, Q., Camenisch, T., Boast, S., Casagranda, F., and Earp, H.S. (1999). Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398, 723-728.   DOI
50 Mills, C.D. (2012). M1 and M2 macrophages: oracles of health and disease. Crit. Rev. Immunol. 32, 463-488.   DOI
51 Mills, C.D., and Ley, K. (2014). M1 and M2 macrophages: the chicken and the egg of immunity. J. Innate. Immun. 6, 716-726.   DOI
52 Mills, C.D., Kincaid, K., Alt, J.M., Heilman, M.J., and Hill, A.M. (2000). M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166-6173.   DOI
53 Mosser, D.M., and Edwards, J.P. (2008). Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958-969.   DOI
54 Alciato, F., Sainaghi, P.P., Sola, D., Castello, L., and Avanzi, G.C. (2010). TNF-alpha, IL-6, and IL-1 expression is inhibited by Gas6 in monocytes/macrophages. J. Leukoc. Biol. 87, 869-875.   DOI
55 Behrens, E.M., Gadue, P., Gong, S.Y., Garrett, S., Stein, P.L., and Cohen, P.L. (2003). The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity. Eur. J. Immunol. 33, 2160-2167.   DOI
56 Ubil, E., Caskey, L., Holtzhausen, A., Hunter, D., Story, C., and Earp, H.S. (2018). Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J. Clin. Invest. 128, 2356-2369.   DOI
57 Stutz, A., Golenbock, D.T., and Latz, E. (2009). Inflammasomes: too big to miss. J. Clin. Invest. 119, 3502-3511.   DOI
58 Takeuchi, O., and Akira, S. (2010). Pattern recognition receptors and inflammation. Cell 140, 805-820.   DOI
59 Todt, J.C., Hu, B., and Curtis, J.L. (2004). The receptor tyrosine kinase MerTK activates phospholipase C gamma2 during recognition of apoptotic thymocytes by murine macrophages. J. Leukoc. Biol. 75, 705-713.   DOI
60 Wu, G., Ma, Z., Cheng, Y., Hu, W., Deng, C., Jiang, S., Li, T., Chen, F., Yang, Y. (2018). Targeting Gas6/TAM in cancer cells and tumor microenvironment. Mol. Cancer 17, 20.   DOI
61 Wu, Y., Singh, S., Georgescu, M.M., and Birge, R.B. (2005). A role for Mer tyrosine kinase in alphavbeta5 integrin mediated phagocytosis of apoptotic cells. J. Cell Sci. 118, 539-553.   DOI
62 Zhang, L., DeBerge, M., Wang, J., Dangi, A., Zhang, X., Schroth, S., Zhang, Z., Thorp, E.B., and Luo, X. (2018). Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance. Am. J. Transplant. [In press] Available at: https://doi.org/10.1111/ajt.15087   DOI
63 Zhou, R., Yazdi, A.S., Menu, P., and Tschopp, J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221-225.   DOI
64 Nagata, K., Ohashi, K., Nakano, T., Arita, H., Zong, C., Hanafusa, H., and Mizuno, K. (1996). Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J. Biol. Chem. 271, 30022-30027.   DOI