Abstract
Recent progress harkens back to the old theme of immune memory, except this time in the area of innate immunity, to which traditional paradigm only prescribes a rudimentary first-line defense function with no memory. However, both in vitro and in vivo studies reveal that innate leukocytes may adopt distinct activation states such as priming, tolerance, and exhaustion, depending upon the history of prior challenges. The dynamic programming and potential memory of innate leukocytes may have far-reaching consequences in health and disease. This review aims to provide some salient features of innate programing and memory, patho-physiological consequences, underlying mechanisms, and current pressing issues.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Baker, B., Geng, S., Chen, K., Diao, N., Yuan, R., Xu, X., Dougherty, S., Stephenson, C., Xiong, H., Chu, H.W., and Li, L. (2015). Alteration of lysosome fusion and low-grade inflammation mediated by super- low-dose endotoxin. J Biol Chem 290, 6670–6678.
Baker, B., Maitra, U., Geng, S., and Li, L. (2014). Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by super-low dose endotoxin. J Biol Chem 289, 16262–16269.
Chan, C., Li, L., McCall, C.E., and Yoza, B.K. (2005). Endotoxin tolerance disrupts chromatin remodeling and NF-kappaB transactivation at the IL-1beta promoter. J Immunol 175, 461–468.
Chen, K., Geng, S., Yuan, R., Diao, N., Upchurch, Z., and Li, L. (2015). Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality. EBioMedicine 2, 324–333.
Chen, X., El Gazzar, M., Yoza, B.K., and McCall, C.E. (2009a). The NF-kappaB factor RelB and histone H3 lysine methyltransferase G9a directly interact to generate epigenetic silencing in endotoxin tolerance. J Biol Chem 284, 27857–27865.
Chen, X., Yoza, B.K., El Gazzar, M., Hu, J.Y., Cousart, S.L., and McCall, C.E. (2009b). RelB sustains IkappaBalpha expression during endotoxin tolerance. Clin Vaccine Immunol 16, 104–110.
Cheng, S.C., Quintin, J., Cramer, R.A., Shepardson, K.M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E.J., Martens, J.H., Rao, N.A., Aghajanirefah, A., Manjeri, G.R., Li, Y., Ifrim, D.C., Arts, R.J., van der Veer, B.M., Deen, P.M., Logie, C., O’Neill, L.A., Willems, P., van de Veerdonk, F.L., van der Meer, J.W., Ng, A., Joosten, L.A., Wijmenga, C., Stunnenberg, H.G., Xavier, R.J., and Netea, M.G. (2014). mTORand HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684.
Christensen, S.R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R.A., and Shlomchik, M.J. (2006). Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428.
Deng, H., Maitra, U., Morris, M., and Li, L. (2013). Molecular mechanism responsible for the priming of macrophage activation. J Biol Chem 288, 3897–3906.
Eisenbarth, S.C., Piggott, D.A., Huleatt, J.W., Visintin, I., Herrick, C.A., and Bottomly, K. (2002). Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 196, 1645–1651.
Fu, Y., Glaros, T., Zhu, M., Wang, P., Wu, Z., Tyson, J.J., Li, L., and Xing, J. (2012). Network topologies and dynamics leading to endotoxin tolerance and priming in innate immune cells. PLoS Comput Biol 8, e1002526.
Gorden, K.B., Gorski, K.S., Gibson, S.J., Kedl, R.M., Kieper, W.C., Qiu, X., Tomai, M.A., Alkan, S.S., and Vasilakos, J.P. (2005). Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174, 1259–1268.
Gordon, S. (2007). The macrophage: past, present and future. Eur J Immunol 37 Suppl 1, S9–S17.
Gordon, S., and Taylor, P.R. (2005). Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953–964.
Henricson, B.E., Manthey, C.L., Perera, P.Y., Hamilton, T.A., and Vogel, S.N. (1993). Dissociation of lipopolysaccharide (LPS)-inducible gene expression in murine macrophages pretreated with smooth LPS versus monophosphoryl lipid A. Infect Immun 61, 2325–2333.
Hirohashi, N., and Morrison, D.C. (1996). Low-dose lipopolysaccharide (LPS) pretreatment of mouse macrophages modulates LPS-dependent interleukin-6 production in vitro. Infect Immun 64, 1011–1015.
Hong, T., Xing, J., Li, L., and Tyson, J.J. (2012). A simple theoretical framework for understanding heterogeneous differentiation of CD4+ T cells. BMC Syst Biol 6, 66.
Hong, T.X.; Li, L.; Tyson, J. (2011). A mathematical model for the reciprocal differentiation of T helper 17 cells and induced regulatory T cells. PLoS Comput Biol 7, e1002122.
Huang, W., and Glass, C.K. (2010). Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arterioscler Thromb Vasc Biol 30, 1542–1549.
Jacinto, R., Hartung, T., McCall, C., and Li, L. (2002). Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance: distinct alterations in IL-1 receptor-associated kinase. J Immunol 168, 6136–6141.
Kallio, K.A., Buhlin, K., Jauhiainen, M., Keva, R., Tuomainen, A.M., Klinge, B., Gustafsson, A., and Pussinen, P.J. (2008). Lipopolysaccharide associates with pro-atherogenic lipoproteins in periodontitis patients. Innate Immun 14, 247–253.
Kawai, T., and Akira, S. (2007). TLR signaling. Semin Immunol 19, 24–32.
Kopanakis, K., Tzepi, I.M., Pistiki, A., Carrer, D.P., Netea, M.G., Georgitsi, M., Lymperi, M., Droggiti, D.I., Liakakos, T., Machairas, A., and Giamarellos-Bourboulis, E.J. (2013). Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: benefit for lethal peritonitis by Escherichia coli. Cytokine 62, 382–388.
Lawrence, T., and Natoli, G. (2011). Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11, 750–761.
Li, L., Chen, S.F., and Liu, Y. (2009). MAP kinase phosphatase-1, a critical negative regulator of the innate immune response. Int J Clin Exp Med 2, 48–67.
Li, L., Cousart, S., Hu, J., and McCall, C.E. (2000). Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J Biol Chem 275, 23340–23345.
Lu, G., Zhang, R., Geng, S., Peng, L., Jayaraman, P., Chen, C., Xu, F., Yang, J., Li, Q., Zheng, H., Shen, K., Wang, J., Liu, X., Wang, W., Zheng, Z., Qi, C.F., Si, C., He, J.C., Liu, K., Lira, S.A., Sikora, A.G., Li, L., and Xiong, H. (2015). Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun 6, 6676.
Maitra, U., Deng, H., Glaros, T., Baker, B., Capelluto, D.G., Li, Z., and Li, L. (2012). Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide. J Immunol 189, 1014–1023.
Maitra, U., Gan, L., Chang, S., and Li, L. (2011). Low-dose endotoxin induces inflammation by selectively removing nuclear receptors and activating CCAAT/enhancer-binding protein {delta}. J Immunol 186, 4467–4473.
Maitra, U., and Li, L. (2013). Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin. Arterioscler Thromb Vasc Biol 33, 24–33.
Martinez-Lopez, N., Athonvarangkul, D., Mishall, P., Sahu, S., and Singh, R. (2013). Autophagy proteins regulate ERK phosphorylation. Nat commun 4, 2799.
Martinez, F.O., Sica, A., Mantovani, A., and Locati, M. (2008). Macrophage activation and polarization. Front Biosci 13, 453–461.
Medvedev, A.E., Lentschat, A., Wahl, L.M., Golenbock, D.T., and Vogel, S.N. (2002). Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 169, 5209–5216.
Morris, M., Gilliam, E., Button, J., and Li, L. (2014). Dynamic modulation of innate immune response by varying dosages of LPS in human monocytic cells. J Bio Chem 289, 21584–21590.
Morris, M., and Li, L. (2012). Molecular mechanisms and pathological consequences of endotoxin tolerance and priming. Arch Immunol Ther Exp (Warsz) 60, 13–18.
Morris, M.G.E., Li, L. (2015). Innate immune programming by endotoxin and its pathological consequences. Front Immunol 5, 680 1–8.
Mosser, D.M., and Edwards, J.P. (2008). Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969.
Netea, M.G., Quintin, J., and van der Meer, J.W. (2011). Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361.
Noubir, S., Hmama, Z., and Reiner, N.E. (2004). Dual receptors and distinct pathways mediate interleukin-1 receptor-associated kinase degradation in response to lipopolysaccharide. Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase. J Biol Chem 279, 25189–25195.
O’Neill, L.A. (2002). Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol 270, 47–61.
Piao, W., Song, C., Chen, H., Diaz, M.A., Wahl, L.M., Fitzgerald, K.A., Li, L., and Medvedev, A.E. (2009). Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling. J Leukocyte Biol 86, 863–875.
Qiao, Y., Giannopoulou, E.G., Chan, C.H., Park, S.H., Gong, S., Chen, J., Hu, X., Elemento, O., and Ivashkiv, L.B. (2013). Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and toll-like receptor signaling. Immunity 39, 454–469.
Quintin, J., Saeed, S., Martens, J.H., Giamarellos-Bourboulis, E.J., Ifrim, D.C., Logie, C., Jacobs, L., Jansen, T., Kullberg, B.J., Wijmenga, C., Joosten, L.A., Xavier, R.J., van der Meer, J.W., Stunnenberg, H.G., and Netea, M.G. (2012). Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232.
Saeed, S., Quintin, J., Kerstens, H.H., Rao, N.A., Aghajanirefah, A., Matarese, F., Cheng, S.C., Ratter, J., Berentsen, K., van der Ent, M.A., Sharifi, N., Janssen-Megens, E.M., Ter Huurne, M., Mandoli, A., van Schaik, T., Ng, A., Burden, F., Downes, K., Frontini, M., Kumar, V., Giamarellos-Bourboulis, E.J., Ouwehand, W.H., van der Meer, J.W., Joosten, L.A., Wijmenga, C., Martens, J.H., Xavier, R.J., Logie, C., Netea, M.G., and Stunnenberg, H.G. (2014). Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086.
Shaw, A.C., Goldstein, D.R., and Montgomery, R.R. (2013). Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13, 875–887.
Sturm, R. (2002). The effects of obesity, smoking, and drinking on medical problems and costs. Health Aff (Millwood) 21, 245–253.
Su J, Z.T., Tyson J, and Li L (2009). The interleukin-1 receptor-associated kinase M (IRAK-M) selectively inhibits the alternative, instead of the classical NFκB pathway. J Innate Immun, 164–174.
Su, X., Yu, Y., Zhong, Y., Giannopoulou, E.G., Hu, X., Liu, H., Cross, J.R., Rätsch, G., Rice, C.M., and Ivashkiv, L.B. (2015). Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol 16, 838–849.
Surace, M.J., and Li, L. (2013). Potent suppression of arginase 1 expression in murine macrophages by low dose endotoxin. Am J Clin Exp Immunol 2, 117–123.
Vandenbulcke, L., Bachert, C., Van Cauwenberge, P., and Claeys, S. (2006). The innate immune system and its role in allergic disorders. Int Arch Allergy Immunol 139, 159–165.
West, M.A., and Heagy, W. (2002). Endotoxin tolerance: a review. Crit Care Med 30, S64–S73.
Wiesner, P., Choi, S.H., Almazan, F., Benner, C., Huang, W., Diehl, C.J., Gonen, A., Butler, S., Witztum, J.L., Glass, C.K., and Miller, Y.I. (2010). Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappab and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circulat Res 107, 56–65.
Wu, Q., Jiang, D., Huang, C., van Dyk, L.F., Li, L., and Chu, H.W. (2015). Trehalose-mediated autophagy impairs the anti-viral function of human primary airway epithelial cells. PLoS One 10, e0124524.
Yoza, B.K., Hu, J.Y., Cousart, S.L., Forrest, L.M., and McCall, C.E. (2006). Induction of RelB participates in endotoxin tolerance. J Immunol 177, 4080–4085.
Yuan, J., Geng, S., Chen, K., Diao, N., Chu, H.W., and Li, L. (2016). Low-grade inflammatory polarization of monocytes impairs wound healing. J Pathol, in press.
Zhang, X., and Morrison, D.C. (1993). Lipopolysaccharide-induced selective priming effects on tumor necrosis factor alpha and nitric oxide production in mouse peritoneal macrophages. J Exp Med 177, 511–516.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at springerlink.bibliotecabuap.elogim.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Yuan, R., Li, L. Dynamic modulation of innate immunity programming and memory. Sci. China Life Sci. 59, 38–43 (2016). https://doi.org/10.1007/s11427-015-4998-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-015-4998-x