The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

Cancer Letters

Volumn 387, Issue , 2017, Pages 46-60

  Wang, Weijun ^a   Zhang, Yaxing ^b,c   Yang, Ling ^a   Li, Hongliang ^b,c  

^a HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY   (China)

^b WUHAN UNIVERSITY   (China)

^c RENMIN HOSPITAL OF WUHAN UNIVERSITY   (China)

Author keywords

Cancer; Cardiometabolic diseases; Innate immune signaling; PRRs

Indexed keywords

PATHOGEN ASSOCIATED MOLECULAR PATTERN; PATTERN RECOGNITION RECEPTOR;

CANCER GROWTH; CARDIOMETABOLIC DISEASE; DRUG TARGETING; HOMEOSTASIS; HUMAN; INFLAMMATION; INNATE IMMUNITY; MALIGNANT NEOPLASM; NONHUMAN; PHYSICAL DISEASE; PRIORITY JOURNAL; SHORT SURVEY; SIGNAL TRANSDUCTION; ANIMAL; CARDIOVASCULAR DISEASE; IMMUNOLOGY; METABOLIC DISORDER; NEOPLASM;

ANIMALS; CARDIOVASCULAR DISEASES; HUMANS; IMMUNITY, INNATE; METABOLIC DISEASES; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 85003706705     PISSN: 03043835     EISSN: 18727980     Source Type: Journal    
DOI: 10.1016/j.canlet.2016.06.004     Document Type: Review

References (217)

1. [1] Calle, E.E., Rodriguez, C., Walker-Thurmond, K., Thun, M.J., Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med 348 (2003), 1625–1638.
2. [2] Stefan, N., Haring, H.U., Hu, F.B., Schulze, M.B., Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol 4 (2016), 457–467.
3. [3] Trinchieri, G., Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu. Rev. Immunol 30 (2012), 677–706.
4. [4] Coussens, L.M., Werb, Z., Inflammation and cancer. Nature 420 (2002), 860–867.
5. [5] Balkwill, F., Mantovani, A., Inflammation and cancer: back to Virchow?. Lancet 357 (2001), 539–545.
6. [6] Pradere, J.P., Dapito, D.H., Schwabe, R.F., The yin and yang of Toll-like receptors in cancer. Oncogene 33 (2014), 3485–3495.
7. [7] Hotamisligil, G.S., Inflammation and metabolic disorders. Nature 444 (2006), 860–867.
8. [8] Van Gaal, L.F., Mertens, I.L., De Block, C.E., Mechanisms linking obesity with cardiovascular disease. Nature 444 (2006), 875–880.
9. [9] Jin, C., Flavell, R.A., Innate sensors of pathogen and stress: linking inflammation to obesity. J. Allergy Clin. Immunol 132 (2013), 287–294.
10. [10] Akira, S., Uematsu, S., Takeuchi, O., Pathogen recognition and innate immunity. Cell 124 (2006), 783–801.
11. [11] Yaxing, Z., Xiao-Jing, Z., Hongliang, L., Targeting interferon regulatory factor for cardiometabolic diseases: opportunities and challenges. Curr. Drug Targets, 2015 Aug 4. [Epub ahead of print].
12. [12] Yang, L., Inokuchi, S., Roh, Y.S., Song, J., Loomba, R., Park, E.J., et al. Transforming growth factor-beta signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 144 (2013), 1042–1054 e1044.
13. [13] Zhang, X.J., Zhang, P., Li, H., Interferon regulatory factor signalings in cardiometabolic diseases. Hypertension 66 (2015), 222–247.
14. [14] Kawai, T., Akira, S., The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol 11 (2010), 373–384.
15. [15] Kawai, T., Akira, S., Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34 (2011), 637–650.
16. [16] Sancho, D., Reis e Sousa, C., Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu. Rev. Immunol 30 (2012), 491–529.
17. [17] Robinson, M.J., Osorio, F., Rosas, M., Freitas, R.P., Schweighoffer, E., Gross, O., et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J. Exp. Med 206 (2009), 2037–2051.
18. [18] Barbe, F., Douglas, T., Saleh, M., Advances in Nod-like receptors (NLR) biology. Cytokine Growth Factor Rev 25 (2014), 681–697.
19. [19] Minkiewicz, J., de Rivero Vaccari, J.P., Keane, R.W., Human astrocytes express a novel NLRP2 inflammasome. Glia 61 (2013), 1113–1121.
20. [20] Brubaker, S.W., Bonham, K.S., Zanoni, I., Kagan, J.C., Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol 33 (2015), 257–290.
21. [21] Lee, M.S., Kim, Y.J., Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem 76 (2007), 447–480.
22. [22] Fernandes-Alnemri, T., Yu, J.W., Datta, P., Wu, J., Alnemri, E.S., AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458 (2009), 509–513.
23. [23] Li, T., Diner, B.A., Chen, J., Cristea, I.M., Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16. Proc. Natl. Acad. Sci. U.S.A. 109 (2012), 10558–10563.
24. [24] Ishikawa, H., Ma, Z., Barber, G.N., STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461 (2009), 788–792.
25. [25] Ng, A., Xavier, R.J., Leucine-rich repeat (LRR) proteins: integrators of pattern recognition and signaling in immunity. Autophagy 7 (2011), 1082–1084.
26. [26] Lin, S.C., Lo, Y.C., Wu, H., Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465 (2010), 885–890.
27. [27] Tseng, P.H., Matsuzawa, A., Zhang, W., Mino, T., Vignali, D.A., Karin, M., Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat. Immunol 11 (2010), 70–75.
28. [28] Kanayama, A., Seth, R.B., Sun, L., Ea, C.K., Hong, M., Shaito, A., et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol. Cell 15 (2004), 535–548.
29. [29] Minassian, A., Zhang, J., He, S., Zhao, J., Zandi, E., Saito, T., et al. An internally translated MAVS variant exposes its amino-terminal TRAF-binding motifs to deregulate interferon induction. PLoS Pathog, 11, 2015, e1005060.
30. [30] Newton, K., Dixit, V.M., Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol, 4, 2012.
31. [31] Hacker, H., Karin, M., Regulation and function of IKK and IKK-related kinases. Sci. STKE, 2006, 2006, re13.
32. [32] Plato, A., Hardison, S.E., Brown, G.D., Pattern recognition receptors in antifungal immunity. Semin. Immunopathol 37 (2015), 97–106.
33. [33] Deng, Z., Ma, S., Zhou, H., Zang, A., Fang, Y., Li, T., et al. Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. Nat. Immunol 16 (2015), 642–652.
34. [34] Blanco-Menendez, N., Del Fresno, C., Fernandes, S., Calvo, E., Conde-Garrosa, R., Kerr, W.G., et al. SHIP-1 couples to the dectin-1 hemITAM and selectively modulates reactive oxygen species production in dendritic cells in response to Candida albicans. J. Immunol 195 (2015), 4466–4478.
35. [35] Gringhuis, S.I., den Dunnen, J., Litjens, M., van der Vlist, M., Wevers, B., Bruijns, S.C., et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat. Immunol 10 (2009), 203–213.
36. [36] Osorio, F., Reis e Sousa, C., Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity 34 (2011), 651–664.
37. [37] Gross, O., Poeck, H., Bscheider, M., Dostert, C., Hannesschlager, N., Endres, S., et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459 (2009), 433–436.
38. [38] Sato, K., Yang, X.L., Yudate, T., Chung, J.S., Wu, J., Luby-Phelps, K., et al. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses. J. Biol. Chem 281 (2006), 38854–38866.
39. [39] Bi, L., Gojestani, S., Wu, W., Hsu, Y.M., Zhu, J., Ariizumi, K., et al. CARD9 mediates dectin-2-induced IkappaBalpha kinase ubiquitination leading to activation of NF-kappaB in response to stimulation by the hyphal form of Candida albicans. J. Biol. Chem 285 (2010), 25969–25977.
40. [40] Gringhuis, S.I., Wevers, B.A., Kaptein, T.M., van Capel, T.M., Theelen, B., Boekhout, T., et al. Selective C-Rel activation via Malt1 controls anti-fungal T(H)-17 immunity by dectin-1 and dectin-2. PLoS Pathog, 7, 2011, e1001259.
41. [41] Martinon, F., Burns, K., Tschopp, J., The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10 (2002), 417–426.
42. [42] Zhong, Y., Kinio, A., Saleh, M., Functions of NOD-like receptors in human diseases. Front. Immunol, 4, 2013, 333.
43. [43] Martin, B.K., Chin, K.C., Olsen, J.C., Skinner, C.A., Dey, A., Ozato, K., et al. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 6 (1997), 591–600.
44. [44] Bertrand, M.J., Doiron, K., Labbe, K., Korneluk, R.G., Barker, P.A., Saleh, M., Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30 (2009), 789–801.
45. [45] Damgaard, R.B., Nachbur, U., Yabal, M., Wong, W.W., Fiil, B.K., Kastirr, M., et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell 46 (2012), 746–758.
46. [46] Pan, Q., Kravchenko, V., Katz, A., Huang, S., Ii, M., Mathison, J.C., et al. NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway. Infect. Immun 74 (2006), 2121–2127.
47. [47] Travassos, L.H., Carneiro, L.A., Ramjeet, M., Hussey, S., Kim, Y.G., Magalhaes, J.G., et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol 11 (2010), 55–62.
48. [48] Kobayashi, K.S., Chamaillard, M., Ogura, Y., Henegariu, O., Inohara, N., Nunez, G., et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307 (2005), 731–734.
49. [49] Mariathasan, S., Monack, D.M., Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat. Rev. Immunol 7 (2007), 31–40.
50. [50] Kim, Y.K., Shin, J.S., Nahm, M.H., NOD-like receptors in infection, immunity, and diseases. Yonsei Med. J. 57 (2016), 5–14.
51. [51] Chavarria-Smith, J., Vance, R.E., The NLRP1 inflammasomes. Immunol. Rev 265 (2015), 22–34.
52. [52] Goubau, D., Deddouche, S., Reis e Sousa, C., Cytosolic sensing of viruses. Immunity 38 (2013), 855–869.
53. [53] Onoguchi, K., Yoneyama, M., Fujita, T., Retinoic acid-inducible gene-I-like receptors. J. Interferon Cytokine Res 31 (2011), 27–31.
54. [54] Michallet, M.C., Meylan, E., Ermolaeva, M.A., Vazquez, J., Rebsamen, M., Curran, J., et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28 (2008), 651–661.
55. [55] Liu, S., Chen, J., Cai, X., Wu, J., Chen, X., Wu, Y.T., et al. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. Elife, 2, 2013, e00785.
56. [56] Zhong, B., Yang, Y., Li, S., Wang, Y.Y., Li, Y., Diao, F., et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29 (2008), 538–550.
57. [57] Komuro, A., Bamming, D., Horvath, C.M., Negative regulation of cytoplasmic RNA-mediated antiviral signaling. Cytokine 43 (2008), 350–358.
58. [58] Bruns, A.M., Pollpeter, D., Hadizadeh, N., Myong, S., Marko, J.F., Horvath, C.M., ATP hydrolysis enhances RNA recognition and antiviral signal transduction by the innate immune sensor, laboratory of genetics and physiology 2 (LGP2). J. Biol. Chem 288 (2013), 938–946.
59. [59] Khare, S., Ratsimandresy, R.A., de Almeida, L., Cuda, C.M., Rellick, S.L., Misharin, A.V., et al. The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat. Immunol 15 (2014), 343–353.
60. [60] Schattgen, S.A., Fitzgerald, K.A., The PYHIN protein family as mediators of host defenses. Immunol. Rev 243 (2011), 109–118.
61. [61] Johnson, K.E., Chikoti, L., Chandran, B., Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J. Virol 87 (2013), 5005–5018.
62. [62] Elinav, E., Nowarski, R., Thaiss, C.A., Hu, B., Jin, C., Flavell, R.A., Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13 (2013), 759–771.
63. [63] Coussens, L.M., Zitvogel, L., Palucka, A.K., Neutralizing tumor-promoting chronic inflammation: a magic bullet?. Science 339 (2013), 286–291.
64. [64] Vesely, M.D., Kershaw, M.H., Schreiber, R.D., Smyth, M.J., Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol 29 (2011), 235–271.
65. [65] Schreiber, R.D., Old, L.J., Smyth, M.J., Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331 (2011), 1565–1570.
66. [66] Guven Maiorov, E., Keskin, O., Gursoy, A., Nussinov, R., The structural network of inflammation and cancer: merits and challenges. Semin. Cancer Biol 23 (2013), 243–251.
67. [67] Jinushi, M., Yin and yang of tumor inflammation: how innate immune suppressors shape the tumor microenvironments. Int. J. Cancer 135 (2014), 1277–1285.
68. [68] Fukata, M., Chen, A., Vamadevan, A.S., Cohen, J., Breglio, K., Krishnareddy, S., et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133 (2007), 1869–1881.
69. [69] Rakoff-Nahoum, S., Medzhitov, R., Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317 (2007), 124–127.
70. [70] Li, Y., Teo, W.L., Low, M.J., Meijer, L., Sanderson, I., Pettersson, S., et al. Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice. Oncogene 33 (2014), 369–377.
71. [71] Dapito, D.H., Mencin, A., Gwak, G.Y., Pradere, J.P., Jang, M.K., Mederacke, I., et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21 (2012), 504–516.
72. [72] Yu, L.X., Yan, L., Yang, W., Wu, F.Q., Ling, Y., Chen, S.Z., et al. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nat. Commun, 5, 2014, 5256.
73. [73] Zhan, Z., Xie, X., Cao, H., Zhou, X., Zhang, X.D., Fan, H., et al. Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination. Autophagy 10 (2014), 257–268.
74. [74] Wang, Z., Yan, J., Lin, H., Hua, F., Wang, X., Liu, H., et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology 57 (2013), 1869–1881.
75. [75] Kim, S., Takahashi, H., Lin, W.W., Descargues, P., Grivennikov, S., Kim, Y., et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457 (2009), 102–106.
76. [76] Lin, H., Yan, J., Wang, Z., Hua, F., Yu, J., Sun, W., et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice. Hepatology 57 (2013), 171–182.
77. [77] Uenishi, Y., Fujita, Y., Kusunose, N., Yano, I., Sunagawa, M., Comprehensive analysis of mycolic acid subclass and molecular species composition of Mycobacterium bovis BCG Tokyo 172 cell wall skeleton (SMP-105). J. Microbiol. Methods 72 (2008), 149–156.
78. [78] Brandenburg, K., Lindner, B., Schromm, A., Koch, M.H., Bauer, J., Merkli, A., et al. Physicochemical characteristics of triacyl lipid A partial structure OM-174 in relation to biological activity. Eur. J. Biochem 267 (2000), 3370–3377.
79. [79] Netea, M.G., Sutmuller, R., Hermann, C., Van der Graaf, C.A., Van der Meer, J.W., van Krieken, J.H., et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol 172 (2004), 3712–3718.
80. [80] Galli, R., Paone, A., Fabbri, M., Zanesi, N., Calore, F., Cascione, L., et al. Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARbeta and tumor regression. Proc. Natl. Acad. Sci. U.S.A. 110 (2013), 9812–9817.
81. [81] Lee, J., Sayed, N., Hunter, A., Au, K.F., Wong, W.H., Mocarski, E.S., et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151 (2012), 547–558.
82. [82] Shime, H., Matsumoto, M., Oshiumi, H., Tanaka, S., Nakane, A., Iwakura, Y., et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc. Natl. Acad. Sci. U.S.A. 109 (2012), 2066–2071.
83. [83] Burdelya, L.G., Krivokrysenko, V.I., Tallant, T.C., Strom, E., Gleiberman, A.S., Gupta, D., et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320 (2008), 226–230.
84. + T-cell axis. Proc. Natl. Acad. Sci. U.S.A. 113 (2016), E874–E883.
85. [85] Stary, G., Bangert, C., Tauber, M., Strohal, R., Kopp, T., Stingl, G., Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J. Exp. Med 204 (2007), 1441–1451.
86. [86] Ochi, A., Graffeo, C.S., Zambirinis, C.P., Rehman, A., Hackman, M., Fallon, N., et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J. Clin. Invest 122 (2012), 4118–4129.
87. [87] Peng, G., Guo, Z., Kiniwa, Y., Voo, K.S., Peng, W., Fu, T., et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309 (2005), 1380–1384.
88. [88] Lu, H., Dietsch, G.N., Matthews, M.A., Yang, Y., Ghanekar, S., Inokuma, M., et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin. Cancer Res 18 (2012), 499–509.
89. [89] Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317 (2007), 121–124.
90. [90] Cataisson, C., Salcedo, R., Hakim, S., Moffitt, B.A., Wright, L., Yi, M., et al. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. J. Exp. Med 209 (2012), 1689–1702.
91. [91] Ansell, S.M., Hodge, L.S., Secreto, F.J., Manske, M., Braggio, E., Price-Troska, T., et al. Activation of TAK1 by MYD88 L265P drives malignant B-cell growth in non-Hodgkin lymphoma. Blood Cancer J., 4, 2014, e183.
92. [92] Ochi, A., Nguyen, A.H., Bedrosian, A.S., Mushlin, H.M., Zarbakhsh, S., Barilla, R., et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J. Exp. Med 209 (2012), 1671–1687.
93. [93] Xu, P., Sun, Z., Wang, Y., Miao, C., Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-kappaB pathway and JAK/STAT3 pathway to inhibit TNF-alpha and IFN-gamma in hepatocellular carcinoma. Exp. Cell Res 337 (2015), 53–60.
94. [94] Akazawa, T., Ebihara, T., Okuno, M., Okuda, Y., Shingai, M., Tsujimura, K., et al. Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 104 (2007), 252–257.
95. [95] Ngo, V.N., Young, R.M., Schmitz, R., Jhavar, S., Xiao, W., Lim, K.H., et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470 (2011), 115–119.
96. [96] Su, B., Luo, T., Zhu, J., Fu, J., Zhao, X., Chen, L., et al. Interleukin-1beta/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent gankyrin activation during hepatocarcinogenesis. Hepatology 61 (2015), 585–597.
97. [97] Li, Z., Younger, K., Gartenhaus, R., Joseph, A.M., Hu, F., Baer, M.R., et al. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. J. Clin. Invest 125 (2015), 1081–1097.
98. [98] Yang, D., Chen, W., Xiong, J., Sherrod, C.J., Henry, D.H., Dittmer, D.P., Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma. Proc. Natl. Acad. Sci. U.S.A. 111 (2014), E4762–E4768.
99. [99] Wang, H., Flannery, S.M., Dickhofer, S., Huhn, S., George, J., Kubarenko, A.V., et al. A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival. J. Biol. Chem 289 (2014), 23123–23131.
100. [100] Bushell, K.R., Kim, Y., Chan, F.C., Ben-Neriah, S., Jenks, A., Alcaide, M., et al. Genetic inactivation of TRAF3 in canine and human B-cell lymphoma. Blood 125 (2015), 999–1005.
101. [101] Li, W., Peng, C., Lee, M.H., Lim, D., Zhu, F., Fu, Y., et al. TRAF4 is a critical molecule for Akt activation in lung cancer. Cancer Res 73 (2013), 6938–6950.
102. [102] Starczynowski, D.T., Lockwood, W.W., Delehouzee, S., Chari, R., Wegrzyn, J., Fuller, M., et al. TRAF6 is an amplified oncogene bridging the RAS and NF-kappaB pathways in human lung cancer. J. Clin. Invest 121 (2011), 4095–4105.
103. [103] Feng, H., Lopez, G.Y., Kim, C.K., Alvarez, A., Duncan, C.G., Nishikawa, R., et al. EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. J. Clin. Invest 124 (2014), 3741–3756.
104. [104] Chiu, H.W., Lin, S.W., Lin, L.C., Hsu, Y.H., Lin, Y.F., Ho, S.Y., et al. Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett 365 (2015), 229–239.
105. [105] Bettermann, K., Vucur, M., Haybaeck, J., Koppe, C., Janssen, J., Heymann, F., et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17 (2010), 481–496.
106. [106] Inokuchi-Shimizu, S., Park, E.J., Roh, Y.S., Yang, L., Zhang, B., Song, J., et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J. Clin. Invest 124 (2014), 3566–3578.
107. [107] Melisi, D., Xia, Q., Paradiso, G., Ling, J., Moccia, T., Carbone, C., et al. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J. Natl. Cancer Inst 103 (2011), 1190–1204.
108. [108] Singh, A., Sweeney, M.F., Yu, M., Burger, A., Greninger, P., Benes, C., et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 148 (2012), 639–650.
109. [109] Chien, Y., Kim, S., Bumeister, R., Loo, Y.M., Kwon, S.W., Johnson, C.L., et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127 (2006), 157–170.
110. [110] Barbie, D.A., Tamayo, P., Boehm, J.S., Kim, S.Y., Moody, S.E., Dunn, I.F., et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462 (2009), 108–112.
111. [111] Seguin, L., Kato, S., Franovic, A., Camargo, M.F., Lesperance, J., Elliott, K.C., et al. An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat. Cell Biol 16 (2014), 457–468.
112. [112] Kim, J.K., Jung, Y., Wang, J., Joseph, J., Mishra, A., Hill, E.E., et al. TBK1 regulates prostate cancer dormancy through mTOR inhibition. Neoplasia 15 (2013), 1064–1074.
113. [113] He, G., Yu, G.Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17 (2010), 286–297.
114. [114] Sakurai, T., Maeda, S., Chang, L., Karin, M., Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc. Natl. Acad. Sci. U.S.A. 103 (2006), 10544–10551.
115. [115] Shaked, H., Hofseth, L.J., Chumanevich, A., Chumanevich, A.A., Wang, J., Wang, Y., et al. Chronic epithelial NF-kappaB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc. Natl. Acad. Sci. U.S.A. 109 (2012), 14007–14012.
116. [116] Burkitt, M.D., Hanedi, A.F., Duckworth, C.A., Williams, J.M., Tang, J.M., O'Reilly, L.A., et al. NF-kappaB1, NF-kappaB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice. J. Pathol 236 (2015), 326–336.
117. [117] Burkitt, M.D., Williams, J.M., Duckworth, C.A., O'Hara, A., Hanedi, A., Varro, A., et al. Signaling mediated by the NF-kappaB sub-units NF-kappaB1, NF-kappaB2 and c-Rel differentially regulate Helicobacter felis-induced gastric carcinogenesis in C57BL/6 mice. Oncogene 32 (2013), 5563–5573.
118. [118] Vallabhapurapu, S.D., Noothi, S.K., Pullum, D.A., Lawrie, C.H., Pallapati, R., Potluri, V., et al. Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth. Nat. Commun, 6, 2015, 8428.
119. [119] Park, J., Kim, K., Lee, E.J., Seo, Y.J., Lim, S.N., Park, K., et al. Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis. Proc. Natl. Acad. Sci. U.S.A. 104 (2007), 17028–17033.
120. [120] Han, Y.W., Choi, J.Y., Uyangaa, E., Kim, S.B., Kim, J.H., Kim, B.S., et al. Distinct dictation of Japanese encephalitis virus-induced neuroinflammation and lethality via triggering TLR3 and TLR4 signal pathways. PLoS Pathog, 10, 2014, e1004319.
121. [121] Chen, Y., Wright, J., Meng, X., Leppard, K.N., Promyelocytic leukemia protein isoform II promotes transcription factor recruitment to activate interferon beta and interferon-responsive gene expression. Mol. Cell. Biol 35 (2015), 1660–1672.
122. [122] Bailey, C.M., Hendrix, M.J., IRF6 in development and disease: a mediator of quiescence and differentiation. Cell Cycle 7 (2008), 1925–1930.
123. [123] Burchert, A., Cai, D., Hofbauer, L.C., Samuelsson, M.K., Slater, E.P., Duyster, J., et al. Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 103 (2004), 3480–3489.
124. [124] Deng, M., Daley, G.Q., Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Blood 97 (2001), 3491–3497.
125. [125] Zhang, Q., Zhang, L., Li, L., Wang, Z., Ying, J., Fan, Y., et al. Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis. Cancer Lett 354 (2014), 227–234.
126. [126] Harada, H., Kitagawa, M., Tanaka, N., Yamamoto, H., Harada, K., Ishihara, M., et al. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259 (1993), 971–974.
127. [127] Vaughan, P.S., van der Meijden, C.M., Aziz, F., Harada, H., Taniguchi, T., van Wijnen, A.J., et al. Cell cycle regulation of histone H4 gene transcription requires the oncogenic factor IRF-2. J. Biol. Chem 273 (1998), 194–199.
128. [128] Savitsky, D., Tamura, T., Yanai, H., Taniguchi, T., Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol. Immunother 59 (2010), 489–510.
129. [129] Yanai, H., Negishi, H., Taniguchi, T., The IRF family of transcription factors: inception, impact and implications in oncogenesis. Oncoimmunology 1 (2012), 1376–1386.
130. [130] Massimino, M., Vigneri, P., Fallica, M., Fidilio, A., Aloisi, A., Frasca, F., et al. IRF5 promotes the proliferation of human thyroid cancer cells. Mol. Cancer, 11, 2012, 21.
131. [131] Kreher, S., Bouhlel, M.A., Cauchy, P., Lamprecht, B., Li, S., Grau, M., et al. Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc. Natl. Acad. Sci. U.S.A. 111 (2014), E4513–E4522.
132. [132] Zhang, L., Zhang, J., Lambert, Q., Der, C.J., Del Valle, L., Miklossy, J., et al. Interferon regulatory factor 7 is associated with Epstein–Barr virus-transformed central nervous system lymphoma and has oncogenic properties. J. Virol 78 (2004), 12987–12995.
133. [133] Goubau, D., Romieu-Mourez, R., Solis, M., Hernandez, E., Mesplede, T., Lin, R., et al. Transcriptional re-programming of primary macrophages reveals distinct apoptotic and anti-tumoral functions of IRF-3 and IRF-7. Eur. J. Immunol 39 (2009), 527–540.
134. [134] Yan, H., Kamiya, T., Suabjakyong, P., Tsuji, N.M., Targeting C-type lectin receptors for cancer immunity. Front. Immunol, 6, 2015, 408.
135. [135] Leibundgut-Landmann, S., Osorio, F., Brown, G.D., Reis e Sousa, C., Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 112 (2008), 4971–4980.
136. [136] Chiba, S., Ikushima, H., Ueki, H., Yanai, H., Kimura, Y., Hangai, S., et al. Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses. eLife, 3, 2014, e04177.
137. [137] Seifert, L., Deutsch, M., Alothman, S., Alqunaibit, D., Werba, G., Pansari, M., et al. Dectin-1 regulates hepatic fibrosis and hepatocarcinogenesis by suppressing TLR4 signaling pathways. Cell Rep 13 (2015), 1909–1921.
138. [138] Friedberg, J.W., Sharman, J., Sweetenham, J., Johnston, P.B., Vose, J.M., Lacasce, A., et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115 (2010), 2578–2585.
139. [139] Cheng, S., Coffey, G., Zhang, X.H., Shaknovich, R., Song, Z., Lu, P., et al. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood 118 (2011), 6342–6352.
140. [140] Fotheringham, J.A., Coalson, N.E., Raab-Traub, N., Epstein–Barr virus latent membrane protein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through alphav-integrin membrane translocation. J. Virol 86 (2012), 10308–10320.
141. [141] Udyavar, A.R., Hoeksema, M.D., Clark, J.E., Zou, Y., Tang, Z., Li, Z., et al. Co-expression network analysis identifies spleen tyrosine kinase (SYK) as a candidate oncogenic driver in a subset of small-cell lung cancer. BMC Syst. Biol, 7(Suppl. 5), 2013, S1.
142. [142] Wei, W., Birrer, M.J., Spleen tyrosine kinase confers paclitaxel resistance in ovarian cancer. Cancer Cell 28 (2015), 7–9.
143. [143] Yuan, Y., Wang, J., Li, J., Wang, L., Li, M., Yang, Z., et al. Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin. Cancer Res 12 (2006), 6687–6695.
144. [144] Zhang, X., Shrikhande, U., Alicie, B.M., Zhou, Q., Geahlen, R.L., Role of the protein tyrosine kinase Syk in regulating cell–cell adhesion and motility in breast cancer cells. Mol. Cancer Res 7 (2009), 634–644.
145. [145] Yang, M., Shao, J.H., Miao, Y.J., Cui, W., Qi, Y.F., Han, J.H., et al. Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell Death Differ 21 (2014), 1290–1302.
146. [146] Knies, N., Alankus, B., Weilemann, A., Tzankov, A., Brunner, K., Ruff, T., et al. Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-kappaB and JNK activation. Proc. Natl. Acad. Sci. U.S.A. 112 (2015), E7230–E7238.
147. [147] Fontan, L., Yang, C., Kabaleeswaran, V., Volpon, L., Osborne, M.J., Beltran, E., et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 22 (2012), 812–824.
148. [148] Kuo, S.H., Chen, L.T., Yeh, K.H., Wu, M.S., Hsu, H.C., Yeh, P.Y., et al. Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J. Clin. Oncol 22 (2004), 3491–3497.
149. [149] Ye, H., Gong, L., Liu, H., Ruskone-Fourmestraux, A., de Jong, D., Pileri, S., et al. Strong BCL10 nuclear expression identifies gastric MALT lymphomas that do not respond to H. pylori eradication. Gut 55 (2006), 137–138.
150. [150] Luminari, S., Intini, D., Baldini, L., Berti, E., Bertoni, F., Zucca, E., et al. BCL10 gene mutations rarely occur in lymphoid malignancies. Leukemia 14 (2000), 905–908.
151. [151] Du, M.Q., Peng, H., Liu, H., Hamoudi, R.A., Diss, T.C., Willis, T.G., et al. BCL10 gene mutation in lymphoma. Blood 95 (2000), 3885–3890.
152. [152] Allison, C.C., Ferrand, J., McLeod, L., Hassan, M., Kaparakis-Liaskos, M., Grubman, A., et al. Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J. Immunol 190 (2013), 3706–3715.
153. [153] Chen, G.Y., Shaw, M.H., Redondo, G., Nunez, G., The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 68 (2008), 10060–10067.
154. [154] Hnatyszyn, A., Szalata, M., Stanczyk, J., Cichy, W., Slomski, R., Association of c.802C>T polymorphism of NOD2/CARD15 gene with the chronic gastritis and predisposition to cancer in H. pylori infected patients. Exp. Mol. Pathol 88 (2010), 388–393.
155. [155] Kurzawski, G., Suchy, J., Kladny, J., Grabowska, E., Mierzejewski, M., Jakubowska, A., et al. The NOD2 3020insC mutation and the risk of colorectal cancer. Cancer Res 64 (2004), 1604–1606.
156. [156] Couturier-Maillard, A., Secher, T., Rehman, A., Normand, S., De Arcangelis, A., Haesler, R., et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest 123 (2013), 700–711.
157. [157] Allen, I.C., TeKippe, E.M., Woodford, R.M., Uronis, J.M., Holl, E.K., Rogers, A.B., et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med 207 (2010), 1045–1056.
158. [158] Zaki, M.H., Vogel, P., Body-Malapel, M., Lamkanfi, M., Kanneganti, T.D., IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J. Immunol 185 (2010), 4912–4920.
159. [159] Dupaul-Chicoine, J., Arabzadeh, A., Dagenais, M., Douglas, T., Champagne, C., Morizot, A., et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43 (2015), 751–763.
160. [160] Huber, S., Gagliani, N., Zenewicz, L.A., Huber, F.J., Bosurgi, L., Hu, B., et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491 (2012), 259–263.
161. [161] Normand, S., Delanoye-Crespin, A., Bressenot, A., Huot, L., Grandjean, T., Peyrin-Biroulet, L., et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl. Acad. Sci. U.S.A. 108 (2011), 9601–9606.
162. [162] Chen, G.Y., Liu, M., Wang, F., Bertin, J., Nunez, G., A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol 186 (2011), 7187–7194.
163. [163] Hu, B., Elinav, E., Huber, S., Booth, C.J., Strowig, T., Jin, C., et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 21635–21640.
164. [164] Hou, J., Zhou, Y., Zheng, Y., Fan, J., Zhou, W., Ng, I.O., et al. Hepatic RIG-I predicts survival and interferon-alpha therapeutic response in hepatocellular carcinoma. Cancer Cell 25 (2014), 49–63.
165. [165] Li, X.Y., Jiang, L.J., Chen, L., Ding, M.L., Guo, H.Z., Zhang, W., et al. RIG-I modulates Src-mediated AKT activation to restrain leukemic stemness. Mol. Cell 53 (2014), 407–419.
166. [166] Besch, R., Poeck, H., Hohenauer, T., Senft, D., Hacker, G., Berking, C., et al. Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J. Clin. Invest 119 (2009), 2399–2411.
167. [167] Duewell, P., Beller, E., Kirchleitner, S.V., Adunka, T., Bourhis, H., Siveke, J., et al. Targeted activation of melanoma differentiation-associated protein 5 (MDA5) for immunotherapy of pancreatic carcinoma. Oncoimmunology, 4, 2015, e1029698.
168. [168] Roulois, D., Loo Yau, H., Singhania, R., Wang, Y., Danesh, A., Shen, S.Y., et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162 (2015), 961–973.
169. [169] Man, S.M., Zhu, Q., Zhu, L., Liu, Z., Karki, R., Malik, A., et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162 (2015), 45–58.
170. [170] Wilson, J.E., Petrucelli, A.S., Chen, L., Koblansky, A.A., Truax, A.D., Oyama, Y., et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat. Med 21 (2015), 906–913.
171. [171] Choubey, D., Deka, R., Ho, S.M., Interferon-inducible IFI16 protein in human cancers and autoimmune diseases. Front. Biosci 13 (2008), 598–608.
172. [172] Yu, F., Hao, X., Zhao, H., Ge, C., Yao, M., Yang, S., et al. Delta-like 1 contributes to cell growth by increasing the interferon-inducible protein 16 expression in hepatocellular carcinoma. Liver Int 30 (2010), 703–714.
173. [173] Zhang, Y., Howell, R.D., Alfonso, D.T., Yu, J., Kong, L., Wittig, J.C., et al. IFI16 inhibits tumorigenicity and cell proliferation of bone and cartilage tumor cells. Front. Biosci 12 (2007), 4855–4863.
174. [174] Corrales, L., Glickman, L.H., McWhirter, S.M., Kanne, D.B., Sivick, K.E., Katibah, G.E., et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 11 (2015), 1018–1030.
175. [175] Ho, S.S., Zhang, W.Y., Tan, N.Y., Khatoo, M., Suter, M.A., Tripathi, S., et al. The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells. Immunity 44 (2016), 1177–1189.
176. [176] Demaria, O., De Gassart, A., Coso, S., Gestermann, N., Di Domizio, J., Flatz, L., et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl. Acad. Sci. U.S.A. 112 (2015), 15408–15413.
177. [177] Fu, J., Kanne, D.B., Leong, M., Glickman, L.H., McWhirter, S.M., Lemmens, E., et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl. Med, 7, 2015, 283ra252.
178. [178] Ahn, J., Xia, T., Konno, H., Konno, K., Ruiz, P., Barber, G.N., Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun, 5, 2014, 5166.
179. [179] Jin, C., Henao-Mejia, J., Flavell, R.A., Innate immune receptors: key regulators of metabolic disease progression. Cell Metab 17 (2013), 873–882.
180. [180] Berg, A.H., Scherer, P.E., Adipose tissue, inflammation, and cardiovascular disease. Circ. Res 96 (2005), 939–949.
181. [181] Jia, L., Vianna, C.R., Fukuda, M., Berglund, E.D., Liu, C., Tao, C., et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat. Commun, 5, 2014, 3878.
182. [182] Jiang, D.S., Zhang, X.F., Gao, L., Zong, J., Zhou, H., Liu, Y., et al. Signal regulatory protein-alpha protects against cardiac hypertrophy via the disruption of toll-like receptor 4 signaling. Hypertension 63 (2014), 96–104.
183. [183] Hua, F., Ha, T., Ma, J., Li, Y., Kelley, J., Gao, X., et al. Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J. Immunol 178 (2007), 7317–7324.
184. [184] Hyakkoku, K., Hamanaka, J., Tsuruma, K., Shimazawa, M., Tanaka, H., Uematsu, S., et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 171 (2010), 258–267.
185. [185] Stienstra, R., van Diepen, J.A., Tack, C.J., Zaki, M.H., van de Veerdonk, F.L., Perera, D., et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 108 (2011), 15324–15329.
186. [186] Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W.Z., Strowig, T., et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482 (2012), 179–185.
187. [187] Duewell, P., Kono, H., Rayner, K.J., Sirois, C.M., Vladimer, G., Bauernfeind, F.G., et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 (2010), 1357–1361.
188. [188] Sandanger, O., Ranheim, T., Vinge, L.E., Bliksoen, M., Alfsnes, K., Finsen, A.V., et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc. Res 99 (2013), 164–174.
189. [189] Yang, F., Wang, Z., Wei, X., Han, H., Meng, X., Zhang, Y., et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J. Cereb. Blood Flow Metab 34 (2014), 660–667.
190. [190] Bracey, N.A., Beck, P.L., Muruve, D.A., Hirota, S.A., Guo, J., Jabagi, H., et al. The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1beta. Exp. Physiol 98 (2013), 462–472.
191. [191] Wang, P.X., Zhang, X.J., Luo, P., Jiang, X., Zhang, P., Guo, J., et al. Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling. Nat. Commun, 7, 2016, 10592.
192. [192] Gong, J., Li, Z.Z., Guo, S., Zhang, X.J., Zhang, P., Zhao, G.N., et al. Neuron-specific tumor necrosis factor receptor-associated factor 3 is a central regulator of neuronal death in acute ischemic stroke. Hypertension 66 (2015), 604–616.
193. [193] Chen, Z., Sheng, L., Shen, H., Zhao, Y., Wang, S., Brink, R., et al. Hepatic TRAF2 regulates glucose metabolism through enhancing glucagon responses. Diabetes 61 (2012), 566–573.
194. [194] Huang, Y., Wu, D., Zhang, X., Jiang, M., Hu, C., Lin, J., et al. Cardiac-specific Traf2 overexpression enhances cardiac hypertrophy through activating AKT/GSK3beta signaling. Gene 536 (2014), 225–231.
195. [195] Yang, K.C., Ma, X., Liu, H., Murphy, J., Barger, P.M., Mann, D.L., et al. Tumor necrosis factor receptor-associated factor 2 mediates mitochondrial autophagy. Circ. Heart Fail 8 (2015), 175–187.
196. [196] Bian, Z., Dai, J., Hiroyasu, N., Guan, H., Yuan, Y., Gan, L., et al. Disruption of tumor necrosis factor receptor associated factor 5 exacerbates pressure overload cardiac hypertrophy and fibrosis. J. Cell. Biochem 115 (2014), 349–358.
197. [197] Wang, L., Lu, Y., Guan, H., Jiang, D., Guan, Y., Zhang, X., et al. Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction. J. Neurochem 126 (2013), 400–414.
198. [198] Dong, L.H., Li, L., Song, Y., Duan, Z.L., Sun, S.G., Lin, Y.L., et al. TRAF6-mediated SM22alpha K21 ubiquitination promotes G6PD activation and NADPH production, contributing to GSH homeostasis and VSMC survival in vitro and in vivo. Circ. Res 117 (2015), 684–694.
199. [199] Guo, S., Li, Z.Z., Jiang, D.S., Lu, Y.Y., Liu, Y., Gao, L., et al. IRF4 is a novel mediator for neuronal survival in ischaemic stroke. Cell Death Differ 21 (2014), 888–903.
200. [200] Jiang, D.S., Li, L., Huang, L., Gong, J., Xia, H., Liu, X., et al. Interferon regulatory factor 1 is required for cardiac remodeling in response to pressure overload. Hypertension 64 (2014), 77–86.
201. [201] Jiang, D.S., Bian, Z.Y., Zhang, Y., Zhang, S.M., Liu, Y., Zhang, R., et al. Role of interferon regulatory factor 4 in the regulation of pathological cardiac hypertrophy. Hypertension 61 (2013), 1193–1202.
202. [202] Wessely, R., Hengst, L., Jaschke, B., Wegener, F., Richter, T., Lupetti, R., et al. A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia. Hum. Mol. Genet 12 (2003), 177–187.
203. [203] Wang, X.A., Zhang, R., She, Z.G., Zhang, X.F., Jiang, D.S., Wang, T., et al. Interferon regulatory factor 3 constrains IKKbeta/NF-kappaB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology 59 (2014), 870–885.
204. [204] Zhang, S.M., Zhu, L.H., Li, Z.Z., Wang, P.X., Chen, H.Z., Guan, H.J., et al. Interferon regulatory factor 3 protects against adverse neo-intima formation. Cardiovasc. Res 102 (2014), 469–479.
205. [205] Lu, J., Bian, Z.Y., Zhang, R., Zhang, Y., Liu, C., Yan, L., et al. Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res. Cardiol, 108, 2013, 326.
206. [206] Huang, L., Zhang, S.M., Zhang, P., Zhang, X.J., Zhu, L.H., Chen, K., et al. Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation. J. Am. Heart Assoc, 3, 2014, e001309.
207. [207] Jiang, D.S., Liu, Y., Zhou, H., Zhang, Y., Zhang, X.D., Zhang, X.F., et al. Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension 63 (2014), 713–722.
208. [208] Wang, X.A., Zhang, R., Zhang, S., Deng, S., Jiang, D., Zhong, J., et al. Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab 305 (2013), E485–E495.
209. [209] Zhang, S.M., Gao, L., Zhang, X.F., Zhang, R., Zhu, L.H., Wang, P.X., et al. Interferon regulatory factor 8 modulates phenotypic switching of smooth muscle cells by regulating the activity of myocardin. Mol. Cell. Biol 34 (2014), 400–414.
210. [210] Jiang, D.S., Wei, X., Zhang, X.F., Liu, Y., Zhang, Y., Chen, K., et al. IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat. Commun, 5, 2014, 3303.
211. [211] Xiang, M., Wang, L., Guo, S., Lu, Y.Y., Lei, H., Jiang, D.S., et al. Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury. J. Neurochem 129 (2014), 988–1001.
212. [212] Jiang, D.S., Luo, Y.X., Zhang, R., Zhang, X.D., Chen, H.Z., Zhang, Y., et al. Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin. Hypertension 63 (2014), 119–127.
213. [213] Zhang, Y., Liu, X., She, Z.G., Jiang, D.S., Wan, N., Xia, H., et al. Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury. Basic Res. Cardiol, 109, 2014, 434.
214. [214] Zhang, S.M., Zhu, L.H., Chen, H.Z., Zhang, R., Zhang, P., Jiang, D.S., et al. Interferon regulatory factor 9 is critical for neointima formation following vascular injury. Nat. Commun, 5, 2014, 5160.
215. [215] Chen, H.Z., Guo, S., Li, Z.Z., Lu, Y., Jiang, D.S., Zhang, R., et al. A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. J. Neurosci 34 (2014), 11897–11912.
216. [216] Dalmas, E., Toubal, A., Alzaid, F., Blazek, K., Eames, H.L., Lebozec, K., et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat. Med 21 (2015), 610–618.
217. [217] Mann, D.L., Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res 116 (2015), 1254–1268.