Acknowledgments
This study was supported by Shandong Provincial Natural Science Foundation (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82173430, 82230107, 82273545).
References
1. Brubaker, S. W., Bonham, K. S., Zanoni, I., Kagan, J. C. , Innate Immune Pattern Recognition: A Cell Biological Perspective.Annu. Rev. Immunol. 2015; 33 : 257–290. DOI: 10.1146/annurev-immunol-032414-112240.
2. Chou, W.-C., Rampanelli, E., Li, X., Ting, J. P.-Y. , Impact of intracellular innate immune receptors on immunometabolism. Cell Mol Immunol . 2022; 19 : 337–351. DOI: 10.1038/s41423-021-00780-y.
3. Girardin, S. E., Boneca, I. G., Viala, J., Chamaillard, M., Labigne, A., Thomas, G., Philpott, D. J., et al. , Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection. Journal of Biological Chemistry . 2003; 278 : 8869–8872. DOI: 10.1074/jbc.C200651200.
4. Zhang, F.-R., Huang, W., Chen, S.-M., Sun, L.-D., Liu, H., Li, Y., Cui, Y., et al. , Genomewide Association Study of Leprosy. N Engl J Med . 2009; 361 : 2609–2618. DOI: 10.1056/NEJMoa0903753.
5. Ashton, J. J., Seaby, E. G., Beattie, R. M., Ennis, S. ,NOD2 in Crohn’s Disease—Unfinished Business. Journal of Crohn’s and Colitis . 2022: jjac124. DOI: 10.1093/ecco-jcc/jjac124.
6. Barnich, N., Aguirre, J. E., Reinecker, H.-C., Xavier, R., Podolsky, D. K. , Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–κB activation in muramyl dipeptide recognition. Journal of Cell Biology . 2005;170 : 21–26. DOI: 10.1083/jcb.200502153.
7. Iyer, J. K., Coggeshall, K. M. , Cutting Edge: Primary Innate Immune Cells Respond Efficiently to Polymeric Peptidoglycan, but Not to Peptidoglycan Monomers. The Journal of Immunology . 2011;186 : 3841–3845. DOI: 10.4049/jimmunol.1004058.
8. Inohara, N., Chamaillard, M., McDonald, C., Nuñez, G. , NOD-LRR PROTEINS: Role in Host-Microbial Interactions and Inflammatory Disease. Annu. Rev. Biochem. 2005; 74 : 355–383. DOI: 10.1146/annurev.biochem.74.082803.133347.
9. Damiano, J. S., Oliveira, V., Welsh, K., Reed, J. C. , Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochemical Journal . 2004;381 : 213–219. DOI: 10.1042/BJ20031506.
10. Karban, A., Waterman, M., Panhuysen, C. I., Pollak, R. D., Nesher, S., Datta, L., Weiss, B., et al. , NOD2/CARD15 genotype and phenotype differences between Ashkenazi and Sephardic Jews with Crohn’s disease. Am J Gastroenterol . 2004; 99 : 1134–1140. DOI: 10.1111/j.1572-0241.2004.04156.x.
11. Azzam, N., Nounou, H., Alharbi, O., Aljebreen, A., Shalaby, M. , CARD15/NOD2, CD14 and toll-like 4 receptor gene polymorphisms in Saudi patients with Crohn’s Disease. Int J Mol Sci . 2012;13 : 4268–4280. DOI: 10.3390/ijms13044268.
12. Mao, L., Dhar, A., Meng, G., Fuss, I., Montgomery-Recht, K., Yang, Z., Xu, Q., et al. , Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function. Front. Immunol. 2022;13 : 988862. DOI: 10.3389/fimmu.2022.988862.
13. Maharana, J., Maharana, D., Bej, A., Sahoo, B. R., Panda, D., Wadavrao, S. B., Vats, A., et al. , Structural Elucidation of Inter-CARD Interfaces involved in NOD2 Tandem CARD Association and RIP2 Recognition. J. Phys. Chem. B . 2021; 125 : 13349–13365. DOI: 10.1021/acs.jpcb.1c06176.
14. Pellegrini, E., Desfosses, A., Wallmann, A., Schulze, W. M., Rehbein, K., Mas, P., Signor, L., et al. , RIP2 filament formation is required for NOD2 dependent NF-κB signalling. Nat Commun . 2018; 9 : 4043. DOI: 10.1038/s41467-018-06451-3.
15. Kim, Y.-G., Kamada, N., Shaw, M. H., Warner, N., Chen, G. Y., Franchi, L., Núñez, G. , The Nod2 Sensor Promotes Intestinal Pathogen Eradication via the Chemokine CCL2-Dependent Recruitment of Inflammatory Monocytes. Immunity . 2011; 34 : 769–780. DOI: 10.1016/j.immuni.2011.04.013.
16. Stafford, C. A., Gassauer, A.-M., de Oliveira Mann, C. C., Tanzer, M. C., Fessler, E., Wefers, B., Nagl, D., et al. , Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature . 2022. Available at: https://www.nature.com/articles/s41586-022-05125-x. DOI: 10.1038/s41586-022-05125-x.
17. Hu, Y., Song, F., Jiang, H., Nuñez, G., Smith, D. E. , SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain–Dependent Immune Response in Mouse Bone Marrow–Derived Macrophages. The Journal of Immunology . 2018; 201 : 652–662. DOI: 10.4049/jimmunol.1800210.
18. Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Mazière, A., Klumperman, J., et al. , Endosomes are specialized platforms for bacterial sensing and NOD2 signalling.Nature . 2014; 509 : 240–244. DOI: 10.1038/nature13133.
19. Bonham, K. S., Kagan, J. C. , Endosomes as platforms for NOD-like receptor signaling. Cell Host Microbe . 2014;15 : 523–525. DOI: 10.1016/j.chom.2014.05.001.
20. Lee, J., Tattoli, I., Wojtal, K. A., Vavricka, S. R., Philpott, D. J., Girardin, S. E. , pH-dependent Internalization of Muramyl Peptides from Early Endosomes Enables Nod1 and Nod2 Signaling.Journal of Biological Chemistry . 2009; 284 : 23818–23829. DOI: 10.1074/jbc.M109.033670.
21. Ismair, M. G., Vavricka, S. R., Kullak-Ublick, G. A., Fried, M., Mengin-Lecreulx, D., Girardin, S. E. , hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides. Can. J. Physiol. Pharmacol. 2006; 84 : 1313–1319. DOI: 10.1139/y06-076.
22. Vavricka, S. R., Musch, M. W., Chang, J. E., Nakagawa, Y., Phanvijhitsiri, K., Waypa, T. S., Merlin, D., et al. , hPepT1 transports muramyl dipeptide, activating NF-κB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology . 2004; 127 : 1401–1409. DOI: 10.1053/j.gastro.2004.07.024.
23. Mohanan, V., Grimes, C. L. , The Molecular Chaperone HSP70 Binds to and Stabilizes NOD2, an Important Protein Involved in Crohn Disease. Journal of Biological Chemistry . 2014; 289 : 18987–18998. DOI: 10.1074/jbc.M114.557686.
24. Barnich, N., Aguirre, J. E., Reinecker, H.-C., Xavier, R., Podolsky, D. K. , Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–κB activation in muramyl dipeptide recognition. Journal of Cell Biology . 2005;170 : 21–26. DOI: 10.1083/jcb.200502153.
25. Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., et al. , A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature . 2001; 411 : 603–606. DOI: 10.1038/35079114.
26. Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., et al. , Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature . 2001; 411 : 599–603. DOI: 10.1038/35079107.
27. Stevens, C., Henderson, P., Nimmo, E. R., Soares, D. C., Dogan, B., Simpson, K. W., Barrett, J. C., et al. , The intermediate filament protein, vimentin, is a regulator of NOD2 activity. Gut . 2013; 62 : 695–707. DOI: 10.1136/gutjnl-2011-301775.
28. Lipinski, S., Grabe, N., Jacobs, G., Billmann-Born, S., Till, A., Häsler, R., Aden, K., et al. , RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition. Proc. Natl. Acad. Sci. U.S.A.2012; 109 : 21426–21431. DOI: 10.1073/pnas.1209673109.
29. Lu, Y., Zheng, Y., Coyaud, É., Zhang, C., Selvabaskaran, A., Yu, Y., Xu, Z., et al. , Palmitoylation of NOD1 and NOD2 is required for bacterial sensing. Science . 2019; 366 : 460–467. DOI: 10.1126/science.aau6391.
30. Sabbah, A., Chang, T. H., Harnack, R., Frohlich, V., Tominaga, K., Dube, P. H., Xiang, Y., et al. , Activation of innate immune antiviral responses by Nod2. Nat Immunol . 2009;10 : 1073–1080. DOI: 10.1038/ni.1782.
31. Kim, J., Yang, Y. L., Jang, Y.-S. , Human β-defensin 2 is involved in CCR2-mediated Nod2 signal transduction, leading to activation of the innate immune response in macrophages.Immunobiology . 2019; 224 : 502–510. DOI: 10.1016/j.imbio.2019.05.004.
32. Keestra-Gounder, A. M., Byndloss, M. X., Seyffert, N., Young, B. M., Chávez-Arroyo, A., Tsai, A. Y., Cevallos, S. A., et al. , NOD1 and NOD2 signalling links ER stress with inflammation.Nature . 2016; 532 : 394–397. DOI: 10.1038/nature17631.
33. Celli, J., Tsolis, R. M. , Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? Nat Rev Microbiol . 2015; 13 : 71–82. DOI: 10.1038/nrmicro3393.
34. Stevens, C., Henderson, P., Nimmo, E. R., Soares, D. C., Dogan, B., Simpson, K. W., Barrett, J. C., et al. , The intermediate filament protein, vimentin, is a regulator of NOD2 activity. Gut . 2013; 62 : 695–707. DOI: 10.1136/gutjnl-2011-301775.
35. Eitel, J., Krüll, M., Hocke, A. C., N′Guessan, P. D., Zahlten, J., Schmeck, B., Slevogt, H., et al. , β-PIX and Rac1 GTPase Mediate Trafficking and Negative Regulation of NOD2. The Journal of Immunology . 2008; 181 : 2664–2671. DOI: 10.4049/jimmunol.181.4.2664.
36. Legrand-Poels, S., Kustermans, G., Bex, F., Kremmer, E., Kufer, T. A., Piette, J. , Modulation of Nod2-dependent NF-κB signaling by the actin cytoskeleton. Journal of Cell Science . 2007;120 : 1299–1310. DOI: 10.1242/jcs.03424.
37. Hasegawa, M., Fujimoto, Y., Lucas, P. C., Nakano, H., Fukase, K., Núñez, G., Inohara, N. , A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. EMBO J . 2008;27 : 373–383. DOI: 10.1038/sj.emboj.7601962.
38. Bertrand, M. J. M., Doiron, K., Labbé, 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 . 2009; 30 : 789–801. DOI: 10.1016/j.immuni.2009.04.011.
39. Krieg, A., Correa, R. G., Garrison, J. B., Le Negrate, G., Welsh, K., Huang, Z., Knoefel, W. T., et al. , XIAP mediates NOD signaling via interaction with RIP2. Proc. Natl. Acad. Sci. U.S.A. 2009; 106 : 14524–14529. DOI: 10.1073/pnas.0907131106.
40. Damgaard, R. B., Nachbur, U., Yabal, M., Wong, W. W.-L., Fiil, B. K., Kastirr, M., Rieser, E., et al. , The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity. Molecular Cell . 2012; 46 : 746–758. DOI: 10.1016/j.molcel.2012.04.014.
41. Damgaard, R. B., Fiil, B. K., Speckmann, C., Yabal, M., Stadt, U. zur, Bekker‐Jensen, S., Jost, P. J., et al. , Disease‐causing mutations in the XIAP BIR 2 domain impair NOD 2‐dependent immune signalling. EMBO Mol Med . 2013; 5 : 1278–1295. DOI: 10.1002/emmm.201303090.
42. Draber, P., Kupka, S., Reichert, M., Draberova, H., Lafont, E., de Miguel, D., Spilgies, L., et al. , LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes. Cell Reports . 2015; 13 : 2258–2272. DOI: 10.1016/j.celrep.2015.11.009.
43. Fiil, B. K., Damgaard, R. B., Wagner, S. A., Keusekotten, K., Fritsch, M., Bekker-Jensen, S., Mailand, N., et al. , OTULIN Restricts Met1-Linked Ubiquitination to Control Innate Immune Signaling.Molecular Cell . 2013; 50 : 818–830. DOI: 10.1016/j.molcel.2013.06.004.
44. Watanabe, T., Asano, N., Meng, G., Yamashita, K., Arai, Y., Sakurai, T., Kudo, M., et al. , NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. Mucosal Immunology . 2014;7 : 1312–1325. DOI: 10.1038/mi.2014.19.
45. Maeda, S., Hsu, L.-C., Liu, H., Bankston, L. A., Iimura, M., Kagnoff, M. F., Eckmann, L., et al. , Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing.Science . 2005; 307 : 734–738. DOI: 10.1126/science.1103685.
46. Abbott, D. W., Yang, Y., Hutti, J. E., Madhavarapu, S., Kelliher, M. A., Cantley, L. C. , Coordinated Regulation of Toll-Like Receptor and NOD2 Signaling by K63-Linked Polyubiquitin Chains.Molecular and Cellular Biology . 2007; 27 : 6012–6025. DOI: 10.1128/MCB.00270-07.
47. Kanneganti, T.-D., Lamkanfi, M., Núñez, G. , Intracellular NOD-like Receptors in Host Defense and Disease. Immunity . 2007;27 : 549–559. DOI: 10.1016/j.immuni.2007.10.002.
48. Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., et al. , Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature . 2001; 411 : 599–603. DOI: 10.1038/35079107.
49. Tigno-Aranjuez, J. T., Asara, J. M., Abbott, D. W. , Inhibition of RIP2’s tyrosine kinase activity limits NOD2-driven cytokine responses. Genes Dev. 2010; 24 : 2666–2677. DOI: 10.1101/gad.1964410.
50. Hedl, M., Abraham, C. , Nod2-induced autocrine interleukin-1 alters signaling by ERK and p38 to differentially regulate secretion of inflammatory cytokines. Gastroenterology . 2012; 143 : 1530–1543. DOI: 10.1053/j.gastro.2012.08.048.
51. Beynon, V., Cotofana, S., Brand, S., Lohse, P., Mair, A., Wagner, S., Mussack, T., et al. , NOD2/CARD15 genotype influences MDP-induced cytokine release and basal IL-12p40 levels in primary isolated peripheral blood monocytes: Inflammatory Bowel Diseases . 2008; 14 : 1033–1040. DOI: 10.1002/ibd.20441.
52. Davey, M. P., Martin, T. M., Planck, S. R., Lee, J., Zamora, D., Rosenbaum, J. T. , Human endothelial cells express NOD2/CARD15 and increase IL-6 secretion in response to muramyl dipeptide.Microvascular Research . 2006; 71 : 103–107. DOI: 10.1016/j.mvr.2005.11.010.
53. Kim, Y.-G., Kamada, N., Shaw, M. H., Warner, N., Chen, G. Y., Franchi, L., Núñez, G. , The Nod2 Sensor Promotes Intestinal Pathogen Eradication via the Chemokine CCL2-Dependent Recruitment of Inflammatory Monocytes. Immunity . 2011; 34 : 769–780. DOI: 10.1016/j.immuni.2011.04.013.
54. Li, J. , Regulation of IL-8 and IL-1 expression in Crohn’s disease associated NOD2/CARD15 mutations. Human Molecular Genetics . 2004; 13 : 1715–1725. DOI: 10.1093/hmg/ddh182.
55. Jeong, Y.-J., Kang, M.-J., Lee, S.-J., Kim, C.-H., Kim, J.-C., Kim, T.-H., Kim, D.-J., et al. , Nod2 and Rip2 contribute to innate immune responses in mouse neutrophils. Immunology . 2014; 143 : 269–276. DOI: 10.1111/imm.12307.
56. Yang, Y., Yin, C., Pandey, A., Abbott, D., Sassetti, C., Kelliher, M. A. , NOD2 Pathway Activation by MDP or Mycobacterium tuberculosis Infection Involves the Stable Polyubiquitination of Rip2.Journal of Biological Chemistry . 2007; 282 : 36223–36229. DOI: 10.1074/jbc.M703079200.
57. Fridh, V., Rittinger, K. , The tandem CARDs of NOD2: intramolecular interactions and recognition of RIP2. PLoS One . 2012; 7 : e34375. DOI: 10.1371/journal.pone.0034375.
58. Tukhvatulin, A. I., Dzharullaeva, A. S., Tukhvatulina, N. M., Shcheblyakov, D. V., Shmarov, M. M., Dolzhikova, I. V., Stanhope-Baker, P., et al. , Powerful Complex Immunoadjuvant Based on Synergistic Effect of Combined TLR4 and NOD2 Activation Significantly Enhances Magnitude of Humoral and Cellular Adaptive Immune Responses Ahmad R, ed. PLoS ONE . 2016; 11 : e0155650. DOI: 10.1371/journal.pone.0155650.
59. Zhou, H., Coveney, A. P., Wu, M., Huang, J., Blankson, S., Zhao, H., O’Leary, D. P., et al. , Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection. Front. Immunol. 2019; 9 : 3082. DOI: 10.3389/fimmu.2018.03082.
60. Cook, D. N., Pisetsky, D. S., Schwartz, D. A. , Toll-like receptors in the pathogenesis of human disease. Nat Immunol . 2004; 5 : 975–979. DOI: 10.1038/ni1116.
61. Kim, Y.-G., Park, J.-H., Shaw, M. H., Franchi, L., Inohara, N., Núñez, G. , The Cytosolic Sensors Nod1 and Nod2 Are Critical for Bacterial Recognition and Host Defense after Exposure to Toll-like Receptor Ligands. Immunity . 2008; 28 : 246–257. DOI: 10.1016/j.immuni.2007.12.012.
62. Magalhaes, J. G., Fritz, J. H., Le Bourhis, L., Sellge, G., Travassos, L. H., Selvanantham, T., Girardin, S. E., et al. , Nod2-Dependent Th2 Polarization of Antigen-Specific Immunity. J Immunol . 2008; 181 : 7925–7935. DOI: 10.4049/jimmunol.181.11.7925.
63. Magalhaes, J. G., Rubino, S. J., Travassos, L. H., Le Bourhis, L., Duan, W., Sellge, G., Geddes, K., et al. , Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proc. Natl. Acad. Sci. U.S.A. 2011; 108 : 14896–14901. DOI: 10.1073/pnas.1015063108.
64. van Beelen, A. J., Zelinkova, Z., Taanman-Kueter, E. W., Muller, F. J., Hommes, D. W., Zaat, S. A. J., Kapsenberg, M. L.,et al. , Stimulation of the Intracellular Bacterial Sensor NOD2 Programs Dendritic Cells to Promote Interleukin-17 Production in Human Memory T Cells. Immunity . 2007; 27 : 660–669. DOI: 10.1016/j.immuni.2007.08.013.
65. Corridoni, D., Shiraishi, S., Chapman, T., Steevels, T., Muraro, D., Thézénas, M.-L., Prota, G., et al. , NOD2 and TLR2 Signal via TBK1 and PI31 to Direct Cross-Presentation and CD8 T Cell Responses. Front. Immunol. 2019; 10 : 958. DOI: 10.3389/fimmu.2019.00958.
66. Guzelj, S., Weiss, M., Slütter, B., Frkanec, R., Jakopin, Ž. , Covalently Conjugated NOD2/TLR7 Agonists Are Potent and Versatile Immune Potentiators. J. Med. Chem. 2022; 65 : 15085–15101. DOI: 10.1021/acs.jmedchem.2c00808.
67. Travassos, L. H., Carneiro, L. A. M., Ramjeet, M., Hussey, S., Kim, Y.-G., Magalhães, J. G., Yuan, L., et al. , Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol . 2010; 11 : 55–62. DOI: 10.1038/ni.1823.
68. Cooney, R., Baker, J., Brain, O., Danis, B., Pichulik, T., Allan, P., Ferguson, D. J. P., et al. , NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med . 2010; 16 : 90–97. DOI: 10.1038/nm.2069.
69. Lapaquette, P., Bringer, M.-A., Darfeuille-Michaud, A. , Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response: Autophagy controls AIEC replication within macrophages.Cellular Microbiology . 2012; 14 : 791–807. DOI: 10.1111/j.1462-5822.2012.01768.x.
70. Saxena, A., Lopes, F., McKay, D. M. , Reduced intestinal epithelial mitochondrial function enhances in vitro interleukin-8 production in response to commensal Escherichia coli. Inflamm. Res. 2018; 67 : 829–837. DOI: 10.1007/s00011-018-1172-5.
71. Plantinga, T. S., Crisan, T. O., Oosting, M., van de Veerdonk, F. L., de Jong, D. J., Philpott, D. J., van der Meer, J. W. M., et al. , Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut . 2011; 60 : 1229–1235. DOI: 10.1136/gut.2010.228908.
72. Lin, J.-D., Devlin, J. C., Yeung, F., McCauley, C., Leung, J. M., Chen, Y.-H., Cronkite, A., et al. , Rewilding Nod2 and Atg16l1 Mutant Mice Uncovers Genetic and Environmental Contributions to Microbial Responses and Immune Cell Composition. Cell Host Microbe . 2020; 27 : 830-840.e4. DOI: 10.1016/j.chom.2020.03.001.
73. Diamanti, M. A., Gupta, J., Bennecke, M., De Oliveira, T., Ramakrishnan, M., Braczynski, A. K., Richter, B., et al. , IKKα controls ATG16L1 degradation to prevent ER stress during inflammation.Journal of Experimental Medicine . 2017; 214 : 423–437. DOI: 10.1084/jem.20161867.
74. Levy, A., Stedman, A., Deutsch, E., Donnadieu, F., Virgin, H. W., Sansonetti, P. J., Nigro, G. , Innate immune receptor NOD2 mediates LGR5 + intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation. Proc. Natl. Acad. Sci. U.S.A. 2020; 117 : 1994–2003. DOI: 10.1073/pnas.1902788117.
75. Bekkering, S., Domínguez-Andrés, J., Joosten, L. A. B., Riksen, N. P., Netea, M. G. , Trained Immunity: Reprogramming Innate Immunity in Health and Disease. Annu. Rev. Immunol. 2021;39 : 667–693. DOI: 10.1146/annurev-immunol-102119-073855.
76. Kleinnijenhuis, J., Quintin, J., Preijers, F., Joosten, L. A. B., Ifrim, D. C., Saeed, S., Jacobs, C., et al. , Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. U.S.A. 2012; 109 : 17537–17542. DOI: 10.1073/pnas.1202870109.
77. Kleinnijenhuis, J., Quintin, J., Preijers, F., Joosten, L. A. B., Ifrim, D. C., Saeed, S., Jacobs, C., et al. , Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. U.S.A. 2012; 109 : 17537–17542. DOI: 10.1073/pnas.1202870109.
78. Wannigama, D. L., Jacquet, A. , NOD2-dependent BCG-induced trained immunity: A way to regulate innate responses to SARS-CoV2?International Journal of Infectious Diseases . 2020; 101 : 52–55. DOI: 10.1016/j.ijid.2020.09.1429.
79. Petnicki-Ocwieja, T., DeFrancesco, A. S., Chung, E., Darcy, C. T., Bronson, R. T., Kobayashi, K. S., Hu, L. T. , Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance Geijtenbeek T, ed. PLoS ONE . 2011;6 : e17414. DOI: 10.1371/journal.pone.0017414.
80. Saez, A., Herrero-Fernandez, B., Gomez-Bris, R., Sánchez-Martinez, H., Gonzalez-Granado, J. M. , Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci . 2023; 24 : 1526. DOI: 10.3390/ijms24021526.
81. Hedl, M., Li, J., Cho, J. H., Abraham, C. , Chronic stimulation of Nod2 mediates tolerance to bacterial products.Proc. Natl. Acad. Sci. U.S.A. 2007; 104 : 19440–19445. DOI: 10.1073/pnas.0706097104.
82. Lee, K.-H., Biswas, A., Liu, Y.-J., Kobayashi, K. S. , Proteasomal Degradation of Nod2 Protein Mediates Tolerance to Bacterial Cell Wall Components. Journal of Biological Chemistry . 2012;287 : 39800–39811. DOI: 10.1074/jbc.M112.410027.
83. Normand, S., Waldschmitt, N., Neerincx, A., Martinez-Torres, R. J., Chauvin, C., Couturier-Maillard, A., Boulard, O., et al. , Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nat Commun . 2018; 9 : 5338. DOI: 10.1038/s41467-018-07750-5.
84. Bist, P., Cheong, W. S., Ng, A., Dikshit, N., Kim, B.-H., Pulloor, N. K., Khameneh, H. J., et al. , E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP.Nat Commun . 2017; 8 : 15865. DOI: 10.1038/ncomms15865.
85. Hedl, M., Abraham, C. , Secretory Mediators Regulate Nod2-Induced Tolerance in Human Macrophages. Gastroenterology . 2011; 140 : 231–241. DOI: 10.1053/j.gastro.2010.09.009.
86. Petnicki-Ocwieja, T., DeFrancesco, A. S., Chung, E., Darcy, C. T., Bronson, R. T., Kobayashi, K. S., Hu, L. T. , Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance Geijtenbeek T, ed. PLoS ONE . 2011;6 : e17414. DOI: 10.1371/journal.pone.0017414.
87. Liu, J., Xiang, J., Li, X., Blankson, S., Zhao, S., Cai, J., Jiang, Y., et al. , NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection. Sci Rep . 2017; 7 : 40418. DOI: 10.1038/srep40418.
88. Coulombe, F., Divangahi, M., Veyrier, F., de Léséleuc, L., Gleason, J. L., Yang, Y., Kelliher, M. A., et al. , Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med . 2009; 206 : 1709–1716. DOI: 10.1084/jem.20081779.
89. Andreu, N., Phelan, J., de Sessions, P. F., Cliff, J. M., Clark, T. G., Hibberd, M. L. , Primary macrophages and J774 cells respond differently to infection with Mycobacterium tuberculosis.Sci Rep . 2017; 7 : 42225. DOI: 10.1038/srep42225.
90. Brooks, M. N., Rajaram, M. V. S., Azad, A. K., Amer, A. O., Valdivia-Arenas, M. A., Park, J.-H., Núñez, G., et al. , NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages.Cell Microbiol . 2011; 13 : 402–418. DOI: 10.1111/j.1462-5822.2010.01544.x.
91. Flynn, J. L., Goldstein, M. M., Chan, J., Triebold, K. J., Pfeffer, K., Lowenstein, C. J., Schreiber, R., et al. , Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity . 1995;2 : 561–572. DOI: 10.1016/1074-7613(95)90001-2.
92. Bourigault, M.-L., Segueni, N., Rose, S., Court, N., Vacher, R., Vasseur, V., Erard, F., et al. , Relative contribution of IL-1α, IL-1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG. Immun Inflamm Dis . 2013; 1 : 47–62. DOI: 10.1002/iid3.9.
93. Mayer-Barber, K. D., Andrade, B. B., Oland, S. D., Amaral, E. P., Barber, D. L., Gonzales, J., Derrick, S. C., et al. , Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature . 2014; 511 : 99–103. DOI: 10.1038/nature13489.
94. Bohrer, A. C., Tocheny, C., Assmann, M., Ganusov, V. V., Mayer-Barber, K. D. , Cutting Edge: IL-1R1 Mediates Host Resistance to Mycobacterium tuberculosis by Trans-Protection of Infected Cells.J Immunol . 2018; 201 : 1645–1650. DOI: 10.4049/jimmunol.1800438.
95. Pandey, A. K., Yang, Y., Jiang, Z., Fortune, S. M., Coulombe, F., Behr, M. A., Fitzgerald, K. A., et al. , NOD2, RIP2 and IRF5 Play a Critical Role in the Type I Interferon Response to Mycobacterium tuberculosis Cossart P, ed. PLoS Pathog . 2009;5 : e1000500. DOI: 10.1371/journal.ppat.1000500.
96. Dorhoi, A., Yeremeev, V., Nouailles, G., Weiner, J., Jörg, S., Heinemann, E., Oberbeck-Müller, D., et al. , Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics. Eur J Immunol . 2014;44 : 2380–2393. DOI: 10.1002/eji.201344219.
97. Kim, B.-R., Kim, B.-J., Kook, Y.-H., Kim, B.-J. , Phagosome Escape of Rough Mycobacterium abscessus Strains in Murine Macrophage via Phagosomal Rupture Can Lead to Type I Interferon Production and Their Cell-To-Cell Spread. Front Immunol . 2019; 10 : 125. DOI: 10.3389/fimmu.2019.00125.
98. Ruangkiattikul, N., Rys, D., Abdissa, K., Rohde, M., Semmler, T., Tegtmeyer, P.-K., Kalinke, U., et al. , Type I interferon induced by TLR2-TLR4-MyD88-TRIF-IRF3 controls Mycobacterium abscessus subsp. abscessus persistence in murine macrophages via nitric oxide. Int J Med Microbiol . 2019; 309 : 307–318. DOI: 10.1016/j.ijmm.2019.05.007.
99. Ahn, J.-H., Park, J.-Y., Kim, D.-Y., Lee, T.-S., Jung, D.-H., Kim, Y.-J., Lee, Y.-J., et al. , Type I Interferons Are Involved in the Intracellular Growth Control of Mycobacterium abscessus by Mediating NOD2-Induced Production of Nitric Oxide in Macrophages.Front. Immunol. 2021; 12 : 738070. DOI: 10.3389/fimmu.2021.738070.
100. Lienard, J., Nobs, E., Lovins, V., Movert, E., Valfridsson, C., Carlsson, F. , The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms. Proc. Natl. Acad. Sci. U.S.A. 2020;117 : 1160–1166. DOI: 10.1073/pnas.1911646117.
101. Manzanillo, P. S., Shiloh, M. U., Portnoy, D. A., Cox, J. S. , Mycobacterium Tuberculosis Activates the DNA-Dependent Cytosolic Surveillance Pathway within Macrophages. Cell Host & Microbe . 2012; 11 : 469–480. DOI: 10.1016/j.chom.2012.03.007.
102. Zhang, L., Jiang, X., Pfau, D., Ling, Y., Nathan, C. F. , Type I interferon signaling mediates Mycobacterium tuberculosis-induced macrophage death. J Exp Med . 2021; 218 : e20200887. DOI: 10.1084/jem.20200887.
103. Ge, P., Lei, Z., Yu, Y., Lu, Z., Qiang, L., Chai, Q., Zhang, Y., et al. , M. tuberculosis PknG manipulates host autophagy flux to promote pathogen intracellular survival.Autophagy . 2022; 18 : 576–594. DOI: 10.1080/15548627.2021.1938912.
104. Aqdas, M., Singh, S., Amir, M., Maurya, S. K., Pahari, S., Agrewala, J. N. , Cumulative Signaling Through NOD-2 and TLR-4 Eliminates the Mycobacterium Tuberculosis Concealed Inside the Mesenchymal Stem Cells. Front. Cell. Infect. Microbiol. 2021;11 : 669168. DOI: 10.3389/fcimb.2021.669168.
105. Juárez, E., Carranza, C., Hernández-Sánchez, F., León-Contreras, J. C., Hernández-Pando, R., Escobedo, D., Torres, M.,et al. , NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans: Immunity to Infection. Eur. J. Immunol. 2012; 42 : 880–889. DOI: 10.1002/eji.201142105.
106. Chauhan, S., Mandell, M. A., Deretic, V. , IRGM Governs the Core Autophagy Machinery to Conduct Antimicrobial Defense.Molecular Cell . 2015; 58 : 507–521. DOI: 10.1016/j.molcel.2015.03.020.
107. Joosten, S. A., van Meijgaarden, K. E., Arend, S. M., Prins, C., Oftung, F., Korsvold, G. E., Kik, S. V., et al. , Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest . 2018; 128 : 1837–1851. DOI: 10.1172/JCI97508.
108. Eisenhut, M. , Enhanced Innate Immunity as Explanation for Reduced Mycobacterium tuberculosis Infection in Bacillus Calmette-Guérin–immunized Children. Am J Respir Crit Care Med . 2013; 188 : 257–258. DOI: 10.1164/rccm.201301-0060LE.
109. Aaby, P., Benn, C. S. , Saving lives by training innate immunity with bacille Calmette-Guérin vaccine. Proc. Natl. Acad. Sci. U.S.A. 2012; 109 : 17317–17318. DOI: 10.1073/pnas.1215761109.
110. Bickett, T. E., McLean, J., Creissen, E., Izzo, L., Hagan, C., Izzo, A. J., Silva Angulo, F., et al. , Characterizing the BCG Induced Macrophage and Neutrophil Mechanisms for Defense Against Mycobacterium tuberculosis. Front Immunol . 2020; 11 : 1202. DOI: 10.3389/fimmu.2020.01202.
111. Divangahi, M. , Are tolerance and training required to end TB? Nat Rev Immunol . 2018; 18 : 661–663. DOI: 10.1038/s41577-018-0070-y.
112. Khan, N., Pahari, S., Vidyarthi, A., Aqdas, M., Agrewala, J. N. , NOD-2 and TLR-4 Signaling Reinforces the Efficacy of Dendritic Cells and Reduces the Dose of TB Drugs against Mycobacterium tuberculosis . J Innate Immun . 2016;8 : 228–242. DOI: 10.1159/000439591.
113. Khan, N., Vidyarthi, A., Pahari, S., Negi, S., Aqdas, M., Nadeem, S., Agnihotri, T., et al. , Signaling through NOD-2 and TLR-4 Bolsters the T cell Priming Capability of Dendritic cells by Inducing Autophagy. Sci Rep . 2016; 6 : 19084. DOI: 10.1038/srep19084.
114. Aqdas, M., Maurya, S. K., Pahari, S., Singh, S., Khan, N., Sethi, K., Kaur, G., et al. , Immunotherapeutic Role of NOD-2 and TLR-4 Signaling as an Adjunct to Antituberculosis Chemotherapy.ACS Infect Dis . 2021; 7 : 2999–3008. DOI: 10.1021/acsinfecdis.1c00136.
115. Divangahi, M., Mostowy, S., Coulombe, F., Kozak, R., Guillot, L., Veyrier, F., Kobayashi, K. S., et al. , NOD2-Deficient Mice Have Impaired Resistance to Mycobacterium tuberculosis Infection through Defective Innate and Adaptive Immunity.J Immunol . 2008; 181 : 7157–7165. DOI: 10.4049/jimmunol.181.10.7157.
116. Anon , IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection - PubMed. Available at: https://pubmed.ncbi.nlm.nih.gov/34739044/.
117. Marcinek, P., Jha, A. N., Shinde, V., Sundaramoorthy, A., Rajkumar, R., Suryadevara, N. C., Neela, S. K., et al. , LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations Fritz JH, ed. PLoS ONE . 2013; 8 : e73103. DOI: 10.1371/journal.pone.0073103.
118. Grant, A. V., Alter, A., Huong, N. T., Orlova, M., Van Thuc, N., Ba, N. N., Thai, V. H., et al. , Crohn’s Disease Susceptibility Genes are Associated With Leprosy in the Vietnamese Population. Journal of Infectious Diseases . 2012; 206 : 1763–1767. DOI: 10.1093/infdis/jis588.
119. Leturiondo, A. L., Noronha, A. B., Mendonça, C. Y. R., Ferreira, C. de O., Alvarado-Arnez, L. E., Manta, F. S. de N., Bezerra, O. C. de L., et al. , Association of NOD2 and IFNG single nucleotide polymorphisms with leprosy in the Amazon ethnic admixed population Bochud P-Y, ed. PLoS Negl Trop Dis . 2020; 14 : e0008247. DOI: 10.1371/journal.pntd.0008247.
120. Schenk, M., Mahapatra, S., Le, P., Kim, H. J., Choi, A. W., Brennan, P. J., Belisle, J. T., et al. , Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae Ehrt S, ed. Infect Immun . 2016; 84 : 2429–2438. DOI: 10.1128/IAI.00334-16.
121. Behr, M. A., Divangahi, M. , Freund’s adjuvant, NOD2 and mycobacteria. Current Opinion in Microbiology . 2015; 23 : 126–132. DOI: 10.1016/j.mib.2014.11.015.
122. Schenk, M., Krutzik, S. R., Sieling, P. A., Lee, D. J., Teles, R. M. B., Ochoa, M. T., Komisopoulou, E., et al. , NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy. Nat Med . 2012; 18 : 555–563. DOI: 10.1038/nm.2650.