Complement and macrophage crosstalk during process of angiogenesis in tumor progression

Journal of Biomedical Science

D. C. Broering¹  A. M. Assiri²  M. Afzal Khan² 

[1] Organ Transplant Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia;Department Comparative Medicine, King Faisal Specialist Hospital and Research Centre, MBC 03, Riyadh 11211, Kingdom of Saudi Arabia

关键词: Macrophage;    Angiogenesis;    Complement mediated injury;    Tumor progression;   

Others  :  1221455
DOI  :  10.1186/s12929-015-0151-1

 received in 2015-02-23, accepted in 2015-05-25,  发布年份 2015

【 摘 要 】

The complement system, which contains some of the most potent pro-inflammatory mediators in the tissue including the anaphylatoxins C3a and C5a are the vital parts of innate immunity. Complement activation seems to play a more critical role in tumor development, but little attention has been given to the angiogenic balance of the activated complement mediators and macrophage polarization during tumor progression. The tumor growth mainly supported by the infiltration of M2- tumor-associated macrophages, and high levels of C3a and C5a, whereas M1-macrophages contribute to immune-mediated tumor suppression. Macrophages express a cognate receptors for both C3a and C5a on their cell surface, and specific binding of C3a and C5a affects the functional modulation and angiogenic properties. Activation of complement mediators induce angiogenesis, favors an immunosuppressive microenvironment, and activate cancer-associated signaling pathways to assist chronic inflammation. In this review manuscript, we highlighted the specific roles of complement activation and macrophage polarization during uncontrolled angiogenesis in tumor progression, and therefore blocking of complement mediators would be an alternative therapeutic option for treating cancer.

【 授权许可】

   
2015 Khan et al.

【 图 表 】

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【 参考文献 】

• [1]Khan MA. Inflammation signals airway smooth muscle cell proliferation in asthma pathogenesis. Multidiscip Respir Med. 2013; 8(1):11.
• [2]Khan MA, Nicolls MR. Complement-mediated microvascular injury leads to chronic rejection. Adv Exp Med Biol. 2013; 734:233-246.
• [3]Khan MA, Nicolls MR, Surguladze B, Saadoun I. Complement components as potential therapeutic targets for asthma treatment. Respir Med. 2014; 108(4):543-549.
• [4]Kwan WH, van der Touw W, Heeger PS. Complement regulation of T cell immunity. Immunol Res. 2012; 54(1–3):247-253.
• [5]Corrales L, Ajona D, Rafail S, Lasarte JJ, Riezu-Boj JI, Lambris JD et al.. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. J Immunol. 2012; 189(9):4674-4683.
• [6]Pio R, Ajona D, Lambris JD. Complement inhibition in cancer therapy. Semin Immunol. 2013; 25(1):54-64.
• [7]Pollina EA, Legesse-Miller A, Haley EM, Goodpaster T, Randolph-Habecker J, Coller HA. Regulating the angiogenic balance in tissues. Cell Cycle. 2008; 7(13):2056-2070.
• [8]Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag. 2006; 2(3):213-219.
• [9]Prager GW, Poettler M, Unseld M, Zielinski CC. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Translational Lung Cancer Research. 2012; 1(1):14-25.
• [10]Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002; 282(5):C947-970.
• [11]Gunn L, Ding C, Liu M, Ma Y, Qi C, Cai Y et al.. Opposing roles for complement component C5a in tumor progression and the tumor microenvironment. J Immunol. 2012; 189(6):2985-2994.
• [12]Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Parsa AT. Cancer and the complement cascade. Molecular Cancer Research: MCR. 2010; 8(11):1453-1465.
• [13]Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C et al.. Modulation of the antitumor immune response by complement. Nat Immunol. 2008; 9(11):1225-1235.
• [14]Sayegh ET, Bloch O, Parsa AT. Complement anaphylatoxins as immune regulators in cancer. Cancer Medicine. 2014; 3(4):747-758.
• [15]Jurianz K, Ziegler S, Garcia-Schuler H, Kraus S, Bohana-Kashtan O, Fishelson Z et al.. Complement resistance of tumor cells: basal and induced mechanisms. Mol Immunol. 1999; 36(13–14):929-939.
• [16]Gasque P, Morgan BP. Complement regulatory protein expression by a human oligodendrocyte cell line: cytokine regulation and comparison with astrocytes. Immunology. 1996; 89(3):338-347.
• [17]Gasque P, Thomas A, Fontaine M, Morgan BP. Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. J Neuroimmunol. 1996; 66(1–2):29-40.
• [18]Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005; 23:821-852.
• [19]Sarma VJ, Huber-Lang M, Ward PA. Complement in lung disease. Autoimmunity. 2006; 39(5):387-394.
• [20]Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M. Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol. 2003; 40(2–4):109-123.
• [21]Gancz D, Fishelson Z. Cancer resistance to complement-dependent cytotoxicity (CDC): Problem-oriented research and development. Mol Immunol. 2009; 46(14):2794-2800.
• [22]Kolev M, Towner L, Donev R. Complement in cancer and cancer immunotherapy. Arch Immunol Ther Exp (Warsz). 2011; 59(6):407-419.
• [23]Gminski J, Mykala-Ciesla J, Machalski M, Drozdz M, Najda J. Immunoglobulins and complement components levels in patients with lung cancer. Romanian Journal of Internal Medicine =Revue roumaine de medecine interne. 1992; 30(1):39-44.
• [24]Bjorge L, Hakulinen J, Vintermyr OK, Jarva H, Jensen TS, Iversen OE et al.. Ascitic complement system in ovarian cancer. Br J Cancer. 2005; 92(5):895-905.
• [25]Deng H, Guo RF, Li WM, Zhao M, Lu YY. Matrix metalloproteinase 11 depletion inhibits cell proliferation in gastric cancer cells. Biochem Biophys Res Commun. 2005; 326(2):274-281.
• [26]Gionanlis L, Alexopoulos E, Papagianni A, Leontsini M, Memmos D. Fibrotic mechanisms in idiopathic rapidly progressive glomerulonephritis: the role of TGF-beta1 and C5b-9. Ren Fail. 2008; 30(2):239-246.
• [27]Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012; 38(7):904-910.
• [28]Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J. The role of the anaphylatoxins in health and disease. Mol Immunol. 2009; 46(14):2753-2766.
• [29]Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010; 11(9):785-797.
• [30]Ramadori G, Rasokat H, Burger R, Meyer Zum Buschenfelde KH, Bitter-Suermann D. Quantitative determination of complement components produced by purified hepatocytes. Clin Exp Immunol. 1984; 55(1):189-196.
• [31]Mogilenko DA, Kudriavtsev IV, Trulioff AS, Shavva VS, Dizhe EB, Missyul BV et al.. Modified low density lipoprotein stimulates complement C3 expression and secretion via liver X receptor and Toll-like receptor 4 activation in human macrophages. J Biol Chem. 2012; 287(8):5954-5968.
• [32]Katz Y, Strunk RC. Synovial fibroblast-like cells synthesize seven proteins of the complement system. Arthritis Rheum. 1988; 31(11):1365-1370.
• [33]Warren HB, Pantazis P, Davies PF. The third component of complement is transcribed and secreted by cultured human endothelial cells. Am J Pathol. 1987; 129(1):9-13.
• [34]Levi-Strauss M, Mallat M. Primary cultures of murine astrocytes produce C3 and factor B, two components of the alternative pathway of complement activation. J Immunol. 1987; 139(7):2361-2366.
• [35]Choy LN, Rosen BS, Spiegelman BM. Adipsin and an endogenous pathway of complement from adipose cells. J Biol Chem. 1992; 267(18):12736-12741.
• [36]Seya T, Hara T, Matsumoto M, Sugita Y, Akedo H. Complement-mediated tumor cell damage induced by antibodies against membrane cofactor protein (MCP, CD46). J Exp Med. 1990; 172(6):1673-1680.
• [37]Wills-Karp M. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc. 2007; 4(3):247-251.
• [38]Cravedi P, van der Touw W, Heeger PS. Complement regulation of T-cell alloimmunity. Semin Nephrol. 2013; 33(6):565-574.
• [39]Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol. 2004; 5(10):981-986.
• [40]Rutkowski MJ, Sughrue ME, Kane AJ, Ahn BJ, Fang S, Parsa AT. The complement cascade as a mediator of tissue growth and regeneration. Inflammation research: Official Journal of the European Histamine Research Society. 2010; 59(11):897-905.
• [41]Rutkowski MJ, Sughrue ME, Kane AJ, Mills SA, Fang S, Parsa AT. Complement and the central nervous system: emerging roles in development, protection and regeneration. Immunol Cell Biol. 2010; 88(8):781-786.
• [42]Coffelt SB, Lewis CE, Naldini L, Brown JM, Ferrara N, De Palma M. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am J Pathol. 2010; 176(4):1564-1576.
• [43]Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C et al.. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res. 2010; 70(13):5270-5280.
• [44]van der Bij GJ, Bogels M, Oosterling SJ, Kroon J, Schuckmann DT, de Vries HE et al.. Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases. Cancer Lett. 2008; 262(1):77-86.
• [45]Leeper-Woodford SK, Detmer K. Acute hypoxia increases alveolar macrophage tumor necrosis factor activity and alters NF-kappaB expression. Am J Physiol. 1999; 276(6 Pt 1):L909-916.
• [46]Negus RP, Turner L, Burke F, Balkwill FR. Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors. J Leukoc Biol. 1998; 63(6):758-765.
• [47]Royds JA, Dower SK, Qwarnstrom EE, Lewis CE. Response of tumour cells to hypoxia: role of p53 and NFkB. Molecular Pathology: MP. 1998; 51(2):55-61.
• [48]Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol. 2008; 181(6):3733-3739.
• [49]Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002; 196(3):254-265.
• [50]Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005; 5(12):953-964.
• [51]Nathan CF. Secretory products of macrophages. J Clin Invest. 1987; 79(2):319-326.
• [52]Mills CD, Lenz LL, Ley K. Macrophages at the fork in the road to health or disease. Front Immunol. 2015; 6:59.
• [53]Murray PJ, Wynn TA. Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol. 2011; 89(4):557-563.
• [54]Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG et al.. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008; 18(5):349-355.
• [55]Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002; 23(11):549-555.
• [56]Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009; 86(5):1065-1073.
• [57]Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006; 124(2):263-266.
• [58]Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21(4):467-476.
• [59]Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E et al.. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci U S A. 2004; 101(13):4560-4565.
• [60]Mantovani A, Sica A, Allavena P, Garlanda C, Locati M. Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol. 2009; 70(5):325-330.
• [61]Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Cogn Neurosci. 2009; 29(43):13435-13444.
• [62]Lamagna C, Aurrand-Lions M, Imhof BA. Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol. 2006; 80(4):705-713.
• [63]Wang J, Wakeham J, Harkness R, Xing Z. Macrophages are a significant source of type 1 cytokines during mycobacterial infection. J Clin Invest. 1999; 103(7):1023-1029.
• [64]Beck AH, Espinosa I, Edris B, Li R, Montgomery K, Zhu S et al.. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009; 15(3):778-787.
• [65]Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett. 2009; 123(2):97-102.
• [66]Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994; 55(3):410-422.
• [67]Aksamit RR, Falk W, Leonard EJ. Chemotaxis by mouse macrophage cell lines. J Immunol. 1981; 126(6):2194-2199.
• [68]Ong SM, Tan YC, Beretta O, Jiang D, Yeap WH, Tai JJ et al.. Macrophages in human colorectal cancer are pro-inflammatory and prime T cells towards an anti-tumour type-1 inflammatory response. Eur J Immunol. 2012; 42(1):89-100.
• [69]Alves AC, Etxebarria A, Soutar AK, Martin C, Bourbon M. Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia. Hum Mol Genet. 2014; 23(7):1817-1828.
• [70]Cramer T, Johnson RS. A novel role for the hypoxia inducible transcription factor HIF-1alpha: critical regulation of inflammatory cell function. Cell Cycle. 2003; 2(3):192-193.
• [71]Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N et al.. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003; 112(5):645-657.
• [72]Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M et al.. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood. 2006; 107(5):2112-2122.
• [73]Sakai Y, Honda M, Fujinaga H, Tatsumi I, Mizukoshi E, Nakamoto Y et al.. Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Res. 2008; 68(24):10267-10279.
• [74]Shimoyamada H, Yazawa T, Sato H, Okudela K, Ishii J, Sakaeda M et al.. Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells. Am J Pathol. 2010; 177(1):70-83.
• [75]Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Frontiers in Physiology. 2014; 5:75.
• [76]Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest. 2004; 114(5):623-633.
• [77]Khan MA, Jiang X, Dhillon G, Beilke J, Holers VM, Atkinson C et al.. CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants. Circ Res. 2011; 109(11):1290-1301.
• [78]Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012; 35:369-389.
• [79]Langer HF, Chung KJ, Orlova VV, Choi EY, Kaul S, Kruhlak MJ et al.. Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis. Blood. 2010; 116(22):4395-4403.
• [80]Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013; 190(8):3831-3838.
• [81]Mastellos D, Lambris JD. Complement: more than a 'guard' against invading pathogens? Trends Immunol. 2002; 23(10):485-491.
• [82]Niculescu F, Rus H, van Biesen T, Shin ML. Activation of Ras and mitogen-activated protein kinase pathway by terminal complement complexes is G protein dependent. J Immunol. 1997; 158(9):4405-4412.
• [83]Rus H, Niculescu F, Badea T, Shin ML. Terminal complement complexes induce cell cycle entry in oligodendrocytes through mitogen activated protein kinase pathway. Immunopharmacology. 1997; 38(1–2):177-187.
• [84]Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004; 9 Suppl 5:10-17.
• [85]Bluff JE, Brown NJ, Reed MW, Staton CA. Tissue factor, angiogenesis and tumour progression. Breast Cancer Res. 2008; 10(2):204.
• [86]Lucas SD, Karlsson-Parra A, Nilsson B, Grimelius L, Akerstrom G, Rastad J et al.. Tumor-specific deposition of immunoglobulin G and complement in papillary thyroid carcinoma. Hum Pathol. 1996; 27(12):1329-1335.
• [87]Bu X, Zheng Z, Wang C, Yu Y. Significance of C4d deposition in the follicular lymphoma and MALT lymphoma and their relationship with follicular dendritic cells. Pathol Res Pract. 2007; 203(3):163-167.
• [88]Schlesinger M, Broman I, Lugassy G. The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives. Leukemia. 1996; 10(9):1509-1513.
• [89]Kraut EH, Sagone AL. Alternative pathway of complement in multiple myeloma. Am J Hematol. 1981; 11(4):335-345.
• [90]Kalwinsky DK, Urmson JR, Stitzel AE, Spitzer RE. Activation of the alternative pathway of complement in childhood acute lymphoblastic leukemia. J Lab Clin Med. 1976; 88(5):745-756.
• [91]Ytting H, Jensenius JC, Christensen IJ, Thiel S, Nielsen HJ. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer. Scand J Gastroenterol. 2004; 39(7):674-679.
• [92]Bamberg CE, Mackay CR, Lee H, Zahra D, Jackson J, Lim YS et al.. The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. J Biol Chem. 2010; 285(10):7633-7644.
• [93]Li K, Anderson KJ, Peng Q, Noble A, Lu B, Kelly AP et al.. Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood. 2008; 112(13):5084-5094.
• [94]Strainic MG, Liu J, Huang D, An F, Lalli PN, Muqim N et al.. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity. 2008; 28(3):425-435.
• [95]Kobayashi S, Nagaura T, Kimura I, Kimura M. Interferon-gamma-activated macrophages enhance angiogenesis from endothelial cells of rat aorta. Immunopharmacology. 1994; 27(1):23-30.
• [96]Nucera S, Biziato D, De Palma M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int J Dev Biol. 2011; 55(4–5):495-503.
• [97]Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol. 2008; 84(3):623-630.
• [98]Redente EF, Dwyer-Nield LD, Merrick DT, Raina K, Agarwal R, Pao W et al.. Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization. Am J Pathol. 2010; 176(6):2972-2985.
• [99]Schrader J, Herkel J. Chronic liver inflammation dominated by interferon-gamma can prevent hepatocarcinogenesis. Oncoimmunology. 2012; 1(2):222-223.
• [100]Melis JP, Strumane K, Ruuls SR, Beurskens FJ, Schuurman J, Parren PW. Complement in therapy and disease: Regulating the complement system with antibody-based therapeutics. Mol Immunol, 2015.
• [101]Coussens LM, Pollard JW. Leukocytes in mammary development and cancer. Cold Spring Harbor perspectives in biology 3(3), 2011.
• [102]de Rezende LC, Silva IV, Rangel LB, Guimaraes MC. Regulatory T cell as a target for cancer therapy. Arch Immunol Ther Exp (Warsz). 2010; 58(3):179-190.
• [103]Oxnard GR, Binder A, Janne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013; 31(8):1097-1104.
• [104]Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012; 366(26):2517-2519.
• [105]Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-740.
• [106]Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nature reviews. Cancer. 2004; 4(1):45-60.
• [107]Woodruff TM, Nandakumar KS, Tedesco F. Inhibiting the C5-C5a receptor axis. Mol Immunol. 2011; 48(14):1631-1642.
• [108]Cole DS, Morgan BP. Beyond lysis: how complement influences cell fate. Clin Sci. 2003; 104(5):455-466.
• [109]Kraus S, Seger R, Fishelson Z. Involvement of the ERK mitogen-activated protein kinase in cell resistance to complement-mediated lysis. Clin Exp Immunol. 2001; 123(3):366-374.
• [110]Niculescu F, Badea T, Rus H. Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. Atherosclerosis. 1999; 142(1):47-56.
• [111]Tegla CA, Cudrici C, Patel S, Trippe R, Rus V, Niculescu F et al.. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011; 51(1):45-60.
• [112]Zipfel PF. Complement and immune defense: from innate immunity to human diseases. Immunol Lett. 2009; 126(1–2):1-7.