Macrophage PD-L1 strikes back: PD-1/PD-L1 interaction drives macrophages toward regulatory subsets
Author(s)
Yun-Jung Lee,
Young-Hye Moon,
Kyeong Eun Hyung,
Jong-Sun Yoo,
Mi Ji Lee,
Ik Hee Lee,
Byung Sung Go,
Kwang Woo Hwang*
Affiliation(s)
Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University, Seoul, Korea.
Laboratory of Host Defense Modulation, College of Pharmacy, Chung-Ang University, Seoul, Korea.
ABSTRACT
Activated macrophages have been simply de?ned as cells that secrete in?ammatory mediators and kill intracellular pathogens until few years ago. Recent studies have proposed a new classification system to separate activated macrophages based on their functional phenotypes: host defense, wound healing, and immune regulation. Regulatory macrophages can arise following innate or adaptive immune responses and hinder macrophage-mediated host defense and inflammatory functions by inhibiting the production of pro-inflammatory mediators. In this study, we investigated whether PD-1 and PD-L1 interaction between macrophages and T cells alters macrophage activities. Our data provide evidence for PD-1/PD-L1 engagement inducing a regulatory profile in macrophages. Regulatory macrophages derived from PD-L1 signaling lost their host defense activity, which consists of the production of pro-inflammatory cytokine IL-6 and the exhibition of increased IL-10, SPHK1 and LIGHT gene levels in early phases of LPS stimulation. This differentiation seems to occur through excessive activation of TLR4 downstream MAPK signaling pathways. Regulatory macrophages induced from PD-1/PD-L1 interaction decrease inflammatory mediators and produce anti-inflammatory cytokines, so this macrophage subset has been under considerable attention as a possible immune regulation mechanism. Understanding and modulating regulatory macrophages may lead to new approches to treat or prevent auto-immune diseases such as type I diabetes, rheumatic syndrome and hypersensitivity-related diseases, which are concerned with the overproduction of inflammatory cytokines in macroages.
Cite this paper
Lee, Y. , Moon, Y. , Hyung, K. , Yoo, J. , Lee, M. , Lee, I. , Go, B. and Hwang, K. (2013) Macrophage PD-L1 strikes back: PD-1/PD-L1 interaction drives macrophages toward regulatory subsets. Advances in Bioscience and Biotechnology, 4, 19-29. doi: 10.4236/abb.2013.48A3003.
Lee, Y. , Moon, Y. , Hyung, K. , Yoo, J. , Lee, M. , Lee, I. , Go, B. and Hwang, K. (2013) Macrophage PD-L1 strikes back: PD-1/PD-L1 interaction drives macrophages toward regulatory subsets. Advances in Bioscience and Biotechnology, 4, 19-29. doi: 10.4236/abb.2013.48A3003.
References
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Journal of Leukocyte Biology, 84, 988-993. doi:10.1189/jlb.1107774 [27] Fleming, B.D. and Mosser, D.M. (2011) Regulatory macrophages: Setting the threshold for therapy. European Journal of Immunology, 41, 2498-2502. doi:10.1002/eji.201141717 [28] Mosser, D.M. (2003) The many faces of macrophage activation. Journal of Leukocyte Biology, 73, 209-212. doi:10.1189/jlb.0602325 [29] Sternberg, E.M. (2006) Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nature Reviews Immunology, 6, 318-328. doi:10.1038/nri1810 [30] Yi, A.K., Yoon, J.G., Yeo, S.J., Hong, S.C., English, B.K. and Krieg, A.M. (2002) Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: Central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. Journal of Immunology, 168, 4711-4720. [31] Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C. and Puccetti, P. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology, 3, 1097-1101. doi:10.1038/ni846 [32] Pchejetski, D., Nunes, J., Coughlan, K., Lall, H., Pitson, J., Waxman, S.M. and Sumbayev, V.V. (2011) The involvement of sphingosine kinase 1 in LPS-induced Tolllike receptor 4-mediated accumulation of HIF-1 alpha protein, activation of ASK1 and production of the proinflammatory cytokine IL-6. Immunology and Cell Biology, 89, 268-274. doi:10.1038/icb.2010.91 [33] Ma, W., Lim, W., Gee, K., Aucoin, S., Nandan, D., Kozlowski, M., Diaz-Mitoma, F. and Kumar, A. (2001) The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages. Journal of Biological Chemistry, 276, 13664-13674. [34] Okazaki, T., Iwai, Y. and Honjo, T. (2002) New regulatory co-receptors: Inducible co-stimulator and PD-1. Current Opinion in Immunology, 14, 779-782. doi:10.1016/S0952-7915(02)00398-9 [35] Park, J.M., Greten, F.R., Wong, A., Westrick, R.J., Arthur, J.S., Otsu, K., Hoffmann, A., Montminy, M. and Karin, M. (2005) Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis—CREB and NF-kappaB as key regulators. Immunity, 23, 319-329. doi:10.1016/j.immuni.2005.08.010 [36] Lucas, M., Zhang, X., Prasanna, V. and Mosser, D.M. (2005) ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. Journal of Immunology, 175, 469-477. [37] Slack, E.C., Robinson, M.J., Hernanz-Falcon, P., Brown, G.D., Williams, D.L., Schweighoffer, E., Tybulewicz, V.L. and Reis e Sousa, C. (2007) Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimlated with zymosan. European Journal of Immunology, 37, 1600-1612. doi:10.1002/eji.200636830
[1] Montano, A.M., Tsujino, F., Takahata, N. and Satta, Y. (2011) Evolutionary origin of peptidoglycan recognition proteins in vertebrate innate immune system. BMC Evolutionary Biology, 11, 79. doi:10.1186/1471-2148-11-79 [2] Auger, M.J. and Ross, J.A. (1993) The biology of the macrophage. In: Lewis, C.E. and McGee, J.O’D., Eds., The Macrophage, Oxford University Press, Oxford, 1-74. [3] Brem-Exner, B.G., Sattler, C., Hutchinson, J.A., Koehl, K. Kronenberg, G.E., Farkas, S., Inoue, S., Blank, C., Knechtle, S.J., Schlitt, H.J., Fandrich, F. and Geissler, E.K. (2008) Macrophages driven to a novel state of activation have anti-inflammatory properties in mice. Journal of Immunology, 180, 335-349. [4] Stout, R.D. and Suttles, J. (2004) Functional plasticity of macrophages: Reversible adaptation to changing microenvironments. Journal of Leukocyte Biology, 76, 509-513. doi:10.1189/jlb.0504272 [5] Anderson, C.F. and Mosser, D.M. (2002) Cutting edge: Biasing immune responses by directing antigen to macrophage Fc gamma receptors. Journal of Immunology, 168, 3697-3701. [6] Mosser, D.M. and Edwards, J.P. (2008) Exploring the full spectrum of macrophage activation. Nature Reviews Immunology, 8, 958-969. doi:10.1038/nri2448 [7] Zhang, X. and Mosser, D.M. (2008) Macrophage activation by endogenous danger signals. Journal of Pathology, 214, 161-178. doi:10.1002/path.2284 [8] Stout, R.D., Jiang, C., Matta, B., Tietzel, I., Watkins, S.K. and Suttles, J. (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. Journal of Immunology, 175, 342-349. [9] Sharpe, A.H. and Freeman, G.J. (2002) The B7-CD28 superfamily. Nature Reviews Immunology, 2, 116-126. doi:10.1038/nri727 [10] Chen, L., Hussien, Y., Hwang, K.W., Wang, Y., Zhou, P. and Alegre, M.L. (2008) Overexpression of program death-1 in T cells has mild impact on allograft survival. Transplant International, 21, 21-29. [11] Ishida, Y., Agata, Y., Shibahara, K. and Honjo, T. (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO Journal, 11, 3887-3895. [12] Agata, Y., Kawasaki, A., Nishimura, H., Ishida, Y., Tsubata, T., Yagita, H. and Honjo, T. (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. International Immunology, 8, 765-772. doi:10.1093/intimm/8.5.765 [13] Nishimura, H., Agata, Y., Kawasaki, A., Sato, M., Imamura, S., Minato, N., Yagita, H., Nakano, T. and Honjo, T. (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. International Immunology, 8, 773-780. doi:10.1093/intimm/8.5.773 [14] del Rio, M.L., Lucas, C.L., Buhler, L., Rayat, G. and Rodriguez-Barbosa, J.I. (2010) HVEM/LIGHT/BTLA/ CD160 cosignaling pathways as targets for immune regulation. Journal of Leukocyte Biology, 87, 223-235. doi:10.1189/jlb.0809590 [15] Dong, H., Zhu, G., Tamada, K. and Chen, L. (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine, 5, 1365-1369. doi:10.1038/70932 [16] Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L.J., Malenkovich, N., Okazaki, T., Byrne, M.C., Horton, H.F., Fouser, L., Carter, L., Ling, V., Bowman, M.R., Carreno, B.M., Collins, M., Wood, C.R. and Honjo, T. (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Journal of Experimental Medicine, 192, 1027-1034. doi:10.1084/jem.192.7.1027 [17] Latchman, Y., Wood, C.R., Chernova, T., Chaudhary, D., Borde, M., Chernova, I., Iwai, Y., Long, A.J., Brown, J.A., Nunes, R., Greenfield, E.A., Bourque, K., Boussiotis, V.A., Carter, L.L., Carreno, B.M., Malenkovich, N., Nishimura, H., Okazaki, T., Honjo, T., Sharpe, A.H. and Freeman, G.J. (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunology, 2, 261-268. doi:10.1038/85330 [18] Yamazaki, T., Akiba, H., Iwai, H., Matsuda, H., Aoki, M., Tanno, Y., Shin, T., Tsuchiya, H., Pardoll, D.M., Okumura, K., Azuma, M. and Yagita, H. (2002) Expression of programmed death 1 ligands by murine T cells and APC. Journal of Immunology, 169, 5538-5545. [19] Nishimura, H., Minato, N., Nakano, T. and Honjo, T. (1998) Immunological studies on PD-1 deficient mice: Implication of PD-1 as a negative regulator for B cell responses. International Immunology, 10, 1563-1572. doi:10.1093/intimm/10.10.1563 [20] Nishimura, H., Honjo, T. and Minato, N. (2000) Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. Journal of Experimental Medicine, 191, 891-898. doi:10.1084/jem.191.5.891 [21] Blazar, B.R., Taylor, P.A., Panoskaltsis-Mortari, A., Sharpe, A.H. and Vallera, D.A. (1999) Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. Journal of Immunology, 162, 6368-6377. [22] Levine, B.L., Ueda, Y., Craighead, N., Huang, M.L. and June, C.H. (1995) CD28 ligands CD80 (B7-1) and CD86 (B7-2) induce long-term autocrine growth of CD4+ T cells and induce similar patterns of cytokine secretion in vitro. International Immunology, 7, 891-904. doi:10.1093/intimm/7.6.891 [23] Salomon, B. and Bluestone, J.A. (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annual Review of Immunology, 19, 225-252. doi:10.1146/annurev.immunol.19.1.225 [24] Orabona, C., Grohmann, U., Belladonna, M.L., Fallarino, F., Vacca, C., Bianchi, R., Bozza, S., Volpi, C., Salomon, B.L., Fioretti, M.C., Romani, L. and Puccetti, P. (2004) CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nature Immunology, 5, 1134-1142. doi:10.1038/ni1124 [25] Won, T.J., Jung, Y.J., Kwon, S.J., Lee, Y.J., Lee do, I., Min, H., Park, E.S., Joo, S.S. and Hwang, K.W. (2010) Forced expression of programmed death-1 gene on T cell decreased the incidence of type 1 diabetes. Archives of Pharmacal Research, 33, 1825-1833. doi:10.1007/s12272-010-1115-3 [26] Teng, M.W., Swann, J.B., Koebel, C.M., Schreiber, R.D. and Smyth, M.J. (2008) Immune-mediated dormancy: An equilibrium with cancer. Journal of Leukocyte Biology, 84, 988-993. doi:10.1189/jlb.1107774 [27] Fleming, B.D. and Mosser, D.M. (2011) Regulatory macrophages: Setting the threshold for therapy. European Journal of Immunology, 41, 2498-2502. doi:10.1002/eji.201141717 [28] Mosser, D.M. (2003) The many faces of macrophage activation. Journal of Leukocyte Biology, 73, 209-212. doi:10.1189/jlb.0602325 [29] Sternberg, E.M. (2006) Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nature Reviews Immunology, 6, 318-328. doi:10.1038/nri1810 [30] Yi, A.K., Yoon, J.G., Yeo, S.J., Hong, S.C., English, B.K. and Krieg, A.M. (2002) Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: Central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. Journal of Immunology, 168, 4711-4720. [31] Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C. and Puccetti, P. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology, 3, 1097-1101. doi:10.1038/ni846 [32] Pchejetski, D., Nunes, J., Coughlan, K., Lall, H., Pitson, J., Waxman, S.M. and Sumbayev, V.V. (2011) The involvement of sphingosine kinase 1 in LPS-induced Tolllike receptor 4-mediated accumulation of HIF-1 alpha protein, activation of ASK1 and production of the proinflammatory cytokine IL-6. Immunology and Cell Biology, 89, 268-274. doi:10.1038/icb.2010.91 [33] Ma, W., Lim, W., Gee, K., Aucoin, S., Nandan, D., Kozlowski, M., Diaz-Mitoma, F. and Kumar, A. (2001) The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages. Journal of Biological Chemistry, 276, 13664-13674. [34] Okazaki, T., Iwai, Y. and Honjo, T. (2002) New regulatory co-receptors: Inducible co-stimulator and PD-1. Current Opinion in Immunology, 14, 779-782. doi:10.1016/S0952-7915(02)00398-9 [35] Park, J.M., Greten, F.R., Wong, A., Westrick, R.J., Arthur, J.S., Otsu, K., Hoffmann, A., Montminy, M. and Karin, M. (2005) Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis—CREB and NF-kappaB as key regulators. Immunity, 23, 319-329. doi:10.1016/j.immuni.2005.08.010 [36] Lucas, M., Zhang, X., Prasanna, V. and Mosser, D.M. (2005) ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. Journal of Immunology, 175, 469-477. [37] Slack, E.C., Robinson, M.J., Hernanz-Falcon, P., Brown, G.D., Williams, D.L., Schweighoffer, E., Tybulewicz, V.L. and Reis e Sousa, C. (2007) Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimlated with zymosan. European Journal of Immunology, 37, 1600-1612. doi:10.1002/eji.200636830