Tlr signalling augments macrophage bactericidal activity through mitochondrial ros
Open accessAbstract
Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.
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Generation of oxidative stress in pathogen-containing phagosomes of phagocytes is a crucial component of antimicrobial immunity.
“Generation of oxidative stress in pathogen-containing phagosomes of phagocytes, for example, is a crucial component of antimicrobial immunity [58,61,79].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
mtROS production is actively triggered by a number of different stimuli including recognition of pathogens and PAMPs or endogenous molecules such as TNF.
“In recent years, however, several studies have shown that mtROS production is actively triggered by a number of different stimuli including the recognition of pathogens and pathogen-associated molecular patterns (PAMPs) [30,61] or endogenous molecules such as TNF [48,136].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
Mitochondria can be recruited as a source for phagosomal ROS during bacterial infection.
“Not only Nox2 but also mitochondria can be recruited as source for phagosomal ROS during bacterial infection [61].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
ROS have to be produced in direct vicinity of the regulated target and do not excessively saturate the cell until they hit their target at random.
“supporting the observation of other studies that ROS have to be produced in direct vicinity of the regulated target and do not excessively saturate the cell until they hit their target at random [29,30,37,61,125,273].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
Macrophages recruit mitochondria to the phagosome to increase ROS production, overcoming the antioxidative capacities of S.t.
“In response, macrophages recruit mitochondria to the phagosome to increase the ROS production in the phagosome finally overcoming the antioxidative capacities of S.t. (see Figure 5).”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
S.t. infection of BMDM induced mitochondrial recruitment and matrix mtROS production near phagosomes in a TLR-MyD88-TRAF6-dependent manner, and matrix ROS contributed to inactivation of S.t.
“They demonstrated for the first time that S.t. infection of BMDM induced mitochondrial recruitment and matrix mtROS production near phagosomes in a TLR-myeloid differentiation primary response 88 (MyD88)-TNF receptor associated factor 6 (TRAF6)-dependent manner. The matrix ROS production then contributed to the inactivation of S.t.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [61]
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Cites
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207 · see citing works
NOX enzymes and the biology of reactive oxygen
Lambeth, J. D. (2004) · Nature Reviews Immunology · doi:10.1038/nri1312 · Cited by 3,125 · see citing works
Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines
Hoiseth, S. K., & Stocker, B. A. D. (1981) · Nature · doi:10.1038/291238a0 · Cited by 2,088 · see citing works
Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., & Chen, Z. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00126-4 · Cited by 1,872 · see citing works
Extension of murine life span by overexpression of catalase targeted to mitochondria
Schriner, S. E., Linford, N. J., Martin, G. M., Treuting, P., Ogburn, C. E., Emond, M., Coskun, P. E., Ladiges, W., Wolf, N., Van Remmen, H., et al. (2005) · Science · doi:10.1126/science.1106653 · Cited by 1,724 · see citing works
Phagocytosis of Microbes: Complexity in Action
Underhill, D. M., & Ozinsky, A. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.103001.114744 · Cited by 1,124 · see citing works
Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves‐Guerra, M., Goubern, M., Surwit, R. S., et al. (2000) · Nature Genetics · doi:10.1038/82565 · Cited by 1,079 · see citing works
Regulation of Phagosome Maturation by Signals from Toll-Like Receptors
Blander, J. M., & Medzhitov, R. (2004) · Science · doi:10.1126/science.1096158 · Cited by 991 · see citing works
Nonproteolytic Functions of Ubiquitin in Cell Signaling
Chen, Z. J., & Sun, L. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.01.014 · Cited by 921 · see citing works
Recognition and Signaling by Toll-Like Receptors
West, A. P., Koblansky, A. A., & Ghosh, S. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.122303.115827 · Cited by 718 · see citing works
Self-citationHorwitz, M. A. (1983) · The Journal of Experimental Medicine · doi:10.1084/jem.158.4.1319 · Cited by 659 · see citing works
Ubiquitylation in innate and adaptive immunity
Bhoj, V. G., & Chen, Z. J. (2009) · Nature · doi:10.1038/nature07959 · Cited by 639 · see citing works
Shiloh, M. U., MacMicking, J. D., Nicholson, S., Brause, J. E., Potter, S. H., Marino, M., Fang, F. C., Dinauer, M. C., & Nathan, C. (1999) · Immunity · doi:10.1016/s1074-7613(00)80004-7 · Cited by 504 · see citing works
Valdivia, R. H., & Falkow, S. (1996) · Molecular Microbiology · doi:10.1046/j.1365-2958.1996.00120.x · Cited by 486 · see citing works
Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network
Kang, B. H., Plescia, J., Dohi, T., Rosa, J., Doxsey, S., & Altieri, D. C. (2007) · Cell · doi:10.1016/j.cell.2007.08.028 · Cited by 445 · see citing works
Mammalian Mitochondrial Complex I: Biogenesis, Regulation, and Reactive Oxygen Species Generation
Koopman, W. J. H., Nijtmans, L. G. J., Dieteren, C. E. J., Roestenberg, P., Valsecchi, F., Smeitink, J. A. M., & Willems, P. H. G. M. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2743 · Cited by 411 · see citing works
Systematic identification of human mitochondrial disease genes through integrative genomics
Calvo, S. E., Jain, M., Xie, X. S., Sheth, S. A., Chang, B., Goldberger, O., Spinazzola, A., Zeviani, M., Carr, S. A., & Mootha, V. K. (2006) · Nature Genetics · doi:10.1038/ng1776 · Cited by 344 · see citing works
ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway
Kopp, E., Medzhitov, R., Carothers, J., Xiao, C., Douglas, I., Janeway, C. A., & Ghosh, S. (1999) · Genes & Development · doi:10.1101/gad.13.16.2059 · Cited by 334 · see citing works
Self-citationSinai, A. P., Webster, P. C., & Joiner, K. A. (1997) · Journal of Cell Science · doi:10.1242/jcs.110.17.2117 · Cited by 324 · see citing works
On regulation of phagosome maturation and antigen presentation
Blander, J. M., & Medzhitov, R. M. (2006) · Nature Immunology · doi:10.1038/ni1006-1029 · Cited by 310 · see citing works
Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ-induced host defensePreprint
Sonoda, J., Laganière, J., Mehl, I. R., Barish, G. D., Chong, L.-W., Li, X., Scheffler, I. E., Mock, D. C., Bataille, A. R., Robert, F., et al. (2007) · Genes & Development · doi:10.1101/gad.1553007 · Cited by 217 · see citing works
Vogel, R. O., Janssen, R. J. R. J., van den Brand, M. A. M., Dieteren, C. E. J., Verkaart, S., Koopman, W. J. H., Willems, P. H. G. M., Pluk, W., van den Heuvel, L. P. W. J., Smeitink, J. A. M., et al. (2007) · Genes & Development · doi:10.1101/gad.408407 · Cited by 195 · see citing works
Walsh, M. C., Kim, G. K., Maurizio, P. L., Molnar, E. E., & Choi, Y. (2008) · PLoS ONE · doi:10.1371/journal.pone.0004064 · Cited by 175 · see citing works
Self-citationWerling, D., Hope, J. C., Howard, C. J., & Jungi, T. W. (2003) · Immunology · doi:10.1111/j.1365-2567.2004.01781.x · Cited by 143 · see citing works
Oxygen-dependent anti-Salmonella activity of macrophages
Vázquez‐Torres, A., & Fang, F. C. (2001) · Trends in Microbiology · doi:10.1016/s0966-842x(00)01897-7 · Cited by 137 · see citing works
Matsumoto, A., Bessho, H., Uehira, K., & Suda, T. (1991) · Journal of Electron Microscopy · doi:10.1093/oxfordjournals.jmicro.a050908 · Cited by 123 · see citing works
The uncoupling protein 2 modulates the cytokine balance in innate immunity☆
ROUSSET, S., EMRE, Y., JOINLAMBERT, O., HURTAUD, C., RICQUIER, D., & CASSARDDOULCIER, A. (2006) · Cytokine · doi:10.1016/j.cyto.2006.07.012 · Cited by 114 · see citing works
The role of mitochondria in cellular defense against microbial infection
Arnoult, D., Carneiro, L. A. M., Tattoli, I., & Girardin, S. E. (2009) · Seminars in Immunology · doi:10.1016/j.smim.2009.05.009 · Cited by 107 · see citing works
Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesisPreprint
Xiao, C., Shim, J., Klüppel, M., Zhang, S. S.-M., Dong, C., Flavell, R. A., Fu, X.-Y., Wrana, J. L., Hogan, B. L. M., & Ghosh, S. (2003) · Genes & Development · doi:10.1101/gad.1145603 · Cited by 102 · see citing works
Self-citationCooper, M. P., Qu, L., Rohas, L. M., Lin, J. D., Yang, W., Erdjument‐Bromage, H., Tempst, P., & Spiegelman, B. M. (2006) · Genes & Development · doi:10.1101/gad.1483906 · Cited by 100 · see citing works
Self-citationevasion of the NADPH phagocyte oxidase
Vázquez‐Torres, A., & Fang, F. C. (2001) · Microbes and Infection · doi:10.1016/s1286-4579(01)01492-7 · Cited by 95 · see citing works
Isolation and mass spectrometry of transcription factor complexes
Winkler, G. S. (2002) · Methods · doi:10.1016/s1046-2023(02)00030-0 · Cited by 90 · see citing works
Brodsky, I. E., Ghori, N., Falkow, S., & Monack, D. M. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04444.x · Cited by 87 · see citing works
Self-citationAdachi, Y., Kindzelskii, A. L., Petty, A. R., Huang, J.-B., Maeda, N., Yotsumoto, S., Aratani, Y., Ohno, N., & Petty, H. R. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.8.5033 · Cited by 64 · see citing works
Chong, A., Lima, C. A., Allan, D. S. J., Nasrallah, G. K., & Garduño, R. (2009) · Infection and Immunity · doi:10.1128/iai.00150-09 · Cited by 53 · see citing works
Nuclear receptor ERR and coactivator PGC-1 are effectors of IFN--induced host defense
Sonoda, J., Laganière, J., Mehl, I. R., Barish, G. D., Chong, L.-W., Li, X., Scheffler, I. E., Mock, D. C., Bataille, A. R., Robert, F., et al. (2007) · Cited by 30 · see citing works
Remer, K. A., Reimer, T., Brcic, M., et al. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02740.x · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ROS function in redox signaling and oxidative stress
Schieber, M., & Chandel, N. S. (2014) · Current Biology · doi:10.1016/j.cub.2014.03.034 · Cited by 6,931 · see citing works
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · see citing works
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity
Kawai, T., & Akira, S. (2011) · Immunity · doi:10.1016/j.immuni.2011.05.006 · Cited by 3,658 · see citing works
Mittler, R. (2017) · Trends in Plant Science · doi:10.1016/j.tplants.2016.08.002 · Cited by 3,499 · see citing works
Physiological Roles of Mitochondrial Reactive Oxygen Species
Sena, L. A., & Chandel, N. S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.09.025 · Cited by 2,632 · see citing works
Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
Shimada, K., Crother, T. R., Karlin, J., Dagvadorj, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.009 · Cited by 2,282 · see citing works
The metabolic signature of macrophage responses
Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01462 · Cited by 2,021 · see citing works
Cellular mechanisms and physiological consequences of redox-dependent signalling
Holmström, K. M., & Finkel, T. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3801 · Cited by 2,093 · see citing works
Reactive Oxygen Species in Metabolic and Inflammatory Signaling
Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q., & Griendling, K. K. (2018) · Circulation Research · doi:10.1161/circresaha.117.311401 · Cited by 2,081 · see citing works
Microglial <scp>M1/M2</scp> polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070 · see citing works
Crosstalk in NF-κB Signaling Pathways
Oeckinghaus, A., Hayden, M. S., & Ghosh, S. (2011) · Nature Immunology · doi:10.1038/ni.2065 · Cited by 1,942 · see citing works
Self-citationMetabolic reprogramming in macrophages and dendritic cells in innate immunity
Kelly, B., & O'Neill, L. A. (2015) · Cell Research · doi:10.1038/cr.2015.68 · Cited by 1,876 · see citing works
Metabolic Pathways in Immune Cell Activation and Quiescence
Pearce, E. L., & Pearce, E. J. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.005 · Cited by 1,692 · see citing works
Beyond oxidative stress: an immunologist's guide to reactive oxygen species
Nathan, C., & Cunningham-Bussel, A. (2013) · Nature Reviews Immunology · doi:10.1038/nri3423 · Cited by 1,619 · see citing works
Lood, C., Blanco, L. P., Purmalek, M. M., Carmona-Rivera, C., De Ravin, S. S., Smith, C. K., Malech, H. L., Ledbetter, J. A., Elkon, K. B., & Kaplan, M. J. (2016) · Nature Medicine · doi:10.1038/nm.4027 · Cited by 1,570 · see citing works
Mitochondria in innate immune responses
West, A. P., Shadel, G. S., & Ghosh, S. (2011) · Nature Reviews Immunology · doi:10.1038/nri2975 · Cited by 1,376 · see citing works
Self-citationSena, L. A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D. A., Wang, C.-R., Schumacker, P. T., Licht, J. D., Perlman, H., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.10.020 · Cited by 1,338 · see citing works
Mitochondrial dynamics in health and disease: mechanisms and potential targets
Chen, W., Zhao, H., & Li, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01547-9 · Cited by 1,306 · see citing works
New mitochondrial DNA synthesis enables NLRP3 inflammasome activation
Zhong, Z., Liang, S., Sanchez-Lopez, E., He, F., Shalapour, S., Lin, X.-J., Wong, J., Ding, S., Seki, E., Schnabl, B., et al. (2018) · Nature · doi:10.1038/s41586-018-0372-z · Cited by 1,208 · see citing works
Metabolism of Inflammation Limited by AMPK and Pseudo-Starvation
O'Neill, L. A. J., & Hardie, D. G. (2013) · Nature · doi:10.1038/nature11862 · Cited by 1,133 · see citing works
Mitochondrial DNA in innate immune responses and inflammatory pathology
West, A. P., & Shadel, G. S. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.21 · Cited by 1,115 · see citing works
Self-citationBrand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063 · see citing works
Mitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
Mitonuclear communication in homeostasis and stress
Quirós, P. M., Mottis, A., & Auwerx, J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.23 · Cited by 787 · see citing works
The inflammasome: an integrated view
Gross, O., Thomas, C. J., Guarda, G., & Tschopp, J. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01046.x · Cited by 778 · see citing works
Reactive oxygen species (ROS) in macrophage activation and function in diabetes
Rendra, E., Riabov, V., Mossel, D. M., Sevastyanova, T., Harmsen, M. C., & Kzhyshkowska, J. (2019) · Immunobiology · doi:10.1016/j.imbio.2018.11.010 · Cited by 636 · see citing works
Tan, H.-Y., Wang, N., Li, S., Hong, M., Wang, X., & Feng, Y. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2795090 · Cited by 657 · see citing works
Functions of ROS in Macrophages and Antimicrobial Immunity
Herb, M., & Schramm, M. (2021) · Antioxidants · doi:10.3390/antiox10020313 · Cited by 633 · see citing works
Yun, J., & Finkel, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.011 · Cited by 626 · see citing works
Mitochondria as signaling organelles
Chandel, N. S. (2014) · BMC Biology · doi:10.1186/1741-7007-12-34 · Cited by 576 · see citing works
Metformin as adjunct antituberculosis therapy
Singhal, A., Jie, L., Kumar, P., Hong, G. S., Leow, M. K.-S., Paleja, B., Tsenova, L., Kurepina, N., Chen, J., Zolezzi, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009885 · Cited by 547 · see citing works
Park, J., Min, J.-S., Kim, B., Chae, U.-B., Yun, J. W., Choi, M.-S., Kong, I.-K., Chang, K.-T., & Lee, D.-S. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2014.10.016 · Cited by 529 · see citing works
Targeting mitochondria-located circrna scar alleviates nash via reducing mros output
Zhao, Q., Liu, J., Deng, H., Ma, R., Liao, J.-Y., Liang, H., Hu, J., Li, J., Guo, Z., Cai, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.009 · Cited by 469 · see citing works
Mitochondria and cell signalling
Tait, S. W. G., & Green, D. R. (2012) · Journal of Cell Science · doi:10.1242/jcs.099234 · Cited by 453 · see citing works
Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis
Larson-Casey, J. L., Deshane, J. S., Ryan, A. J., Thannickal, V. J., & Carter, A. B. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.001 · Cited by 428 · see citing works
Mitochondria in innate immune signaling
Banoth, B., & Cassel, S. L. (2018) · Translational Research · doi:10.1016/j.trsl.2018.07.014 · Cited by 410 · see citing works
Signal Transduction by Mitochondrial Oxidants
Finkel, T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.271999 · Cited by 390 · see citing works
Wang, F., Zhang, S., Jeon, R., Vuckovic, I., Jiang, X., Lerman, A., Folmes, C. D., Dzeja, P. D., & Herrmann, J. (2018) · eBioMedicine · doi:10.1016/j.ebiom.2018.02.009 · Cited by 339 · see citing works
Cloonan, S. M., & Choi, A. M. K. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81113 · Cited by 322 · see citing works
Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense
Garaude, J., Acín-Pérez, R., Martínez-Cano, S., Enamorado, M., Ugolini, M., Nistal-Villán, E., Hervás-Stubbs, S., Pelegrín, P., Sander, L. E., Enríquez, J. A., et al. (2016) · Nature Immunology · doi:10.1038/ni.3509 · Cited by 313 · see citing works
Gut bacteria signaling to mitochondria in intestinal inflammation and cancer
Jackson, D. N., & Theiss, A. L. (2020) · Gut Microbes · doi:10.1080/19490976.2019.1592421 · Cited by 312 · see citing works
Speer, T., Rohrer, L., Blyszczuk, P., Shroff, R., Kuschnerus, K., Kränkel, N., Kania, G., Zewinger, S., Akhmedov, A., Shi, Y., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.009 · Cited by 310 · see citing works
Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective
Pérez, S., & Rius-Pérez, S. (2022) · Antioxidants · doi:10.3390/antiox11071394 · Cited by 312 · see citing works
Geng, J., Shi, Y., Zhang, J., Yang, B., Wang, P., Yuan, W., Zhao, H., Li, J., Qin, F., Hong, L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23683-y · Cited by 290 · see citing works
Li, H., Zhou, X., Huang, Y., Liao, B., Cheng, L., & Ren, B. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.622534 · Cited by 284 · see citing works
Jin, Z., Wei, W., Yang, M., Du, Y., & Wan, Y. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.011 · Cited by 283 · see citing works
Geng, J., Sun, X., Wang, P., Zhang, S., Wang, X., Wu, H., Hong, L., Xie, C., Li, X., Zhao, H., et al. (2015) · Nature Immunology · doi:10.1038/ni.3268 · Cited by 264 · see citing works
Cameron, A. M., Castoldi, A., Sanin, D. E., Flachsmann, L. J., Field, C. S., Puleston, D. J., Kyle, R. L., Patterson, A. E., Hässler, F., Buescher, J. M., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0336-y · Cited by 269 · see citing works
Hall, C. J., Boyle, R. H., Astin, J. W., Flores, M. V., Oehlers, S. H., Sanderson, L. E., Ellett, F., Lieschke, G. J., Crosier, K. E., & Crosier, P. S. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.018 · Cited by 266 · see citing works
Naujoks, J., Tabeling, C., Dill, B. D., Hoffmann, C., Brown, A. S., Kunze, M., Kempa, S., Peter, A., Mollenkopf, H.-J., Dorhoi, A., et al. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005408 · Cited by 261 · see citing works
Lipid and Lipoprotein Metabolism in Microglia
Loving, B. A., & Bruce, K. D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00393 · Cited by 255 · see citing works
Quigley, J., Hughitt, V. K., Velikovsky, C. A., Mariuzza, R. A., El-Sayed, N. M., & Briken, V. (2017) · mBio · doi:10.1128/mbio.00148-17 · Cited by 234 · see citing works
Nrros negatively regulates reactive oxygen species during host defence and autoimmunity
Noubade, R., Wong, K., Ota, N., Rutz, S., Eidenschenk, C., Valdez, P. A., Ding, J., Peng, I., Sebrell, A., Caplazi, P., et al. (2014) · Nature · doi:10.1038/nature13152 · Cited by 246 · see citing works
Meiser, J., Krämer, L., Sapcariu, S. C., Battello, N., Ghelfi, J., D'Herouel, A. F., Skupin, A., & Hiller, K. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.676817 · Cited by 243 · see citing works
Oxidative Stress and Huntington’s Disease: The Good, the Bad, and the Ugly
Kumar, A., & Ratan, R. R. (2016) · Journal of Huntington s Disease · doi:10.3233/jhd-160205 · Cited by 236 · see citing works
Abuaita, B. H., Schultz, T. L., & O’Riordan, M. X. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.10.005 · Cited by 223 · see citing works
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
Yang, S., Qin, C., Hu, Z.-W., Zhou, L.-Q., Yu, H.-H., Chen, M., Bosco, D. B., Wang, W., Wu, L.-J., & Tian, D.-S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105290 · Cited by 232 · see citing works
The role of mitochondrial dysfunction in age-related diseases
Lane, R. K., Hilsabeck, T., & Rea, S. L. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.05.021 · Cited by 205 · see citing works
Metabolism Supports Macrophage Activation
Langston, P. K., Shibata, M., & Horng, T. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00061 · Cited by 185 · see citing works
Microbiota-mitochondria inter-talk: Consequence for microbiota-host interaction
Saint-Georges-Chaumet, Y., & Edeas, M. (2016) · Pathogens and Disease · doi:10.1093/femspd/ftv096 · Cited by 176 · see citing works
Endosomal nox2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy
To, E. E., Vlahos, R., Luong, R., Halls, M. L., Reading, P. C., King, P. T., Chan, C., Drummond, G. R., Sobey, C. G., Broughton, B. R. S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00057-x · Cited by 154 · see citing works
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Herb, M., Gluschko, A., Wiegmann, K., Farid, A., Wolf, A., Utermöhlen, O., Krut, O., Krönke, M., & Schramm, M. (2019) · Science Signaling · doi:10.1126/scisignal.aar5926 · Cited by 119 · see citing works
Pizzolla, A., Hultqvist, M., Nilson, B., Grimm, M. J., Eneljung, T., Jonsson, I.-M., Verdrengh, M., Kelkka, T., Gjertsson, I., Segal, B. H., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103430 · Cited by 108 · see citing works
Acidification of the intimal fluid: the perfect storm for atherogenesis
Öörni, K., Rajamäki, K., Nguyen, S. D., Lähdesmäki, K., Plihtari, R., Lee-Rueckert, M., & Kovanen, P. T. (2015) · Journal of Lipid Research · doi:10.1194/jlr.r050252 · Cited by 101 · see citing works
Redox implications in adipose tissue (dys)function-A new look at old acquaintances
Jankovic, A., Korac, A., Buzadzic, B., Otasevic, V., Stancic, A., Daiber, A., & Korac, B. (2015) · Redox Biology · doi:10.1016/j.redox.2015.06.018 · Cited by 91 · see citing works
Kumaran, R., & Cookson, M. R. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv236 · Cited by 86 · see citing works
Dectin-1 Activation Controls Maturation of β-1,3-Glucan-containing Phagosomes
Mansour, M. K., Tam, J. M., Khan, N. S., Seward, M., Davids, P. J., Puranam, S., Sokolovska, A., Sykes, D. B., Dagher, Z., Becker, C., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.473223 · Cited by 85 · see citing works
Powering the Immune System: Mitochondria in Immune Function and Deficiency
Walker, M. A., Volpi, S., Sims, K. B., Walter, J. E., & Traggiai, E. (2014) · Journal of Immunology Research · doi:10.1155/2014/164309 · Cited by 83 · see citing works
miR-15a/16 Regulates Macrophage Phagocytosis after Bacterial Infection
Moon, H.-G., Yang, J., Zheng, Y., & Jin, Y. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401372 · Cited by 81 · see citing works
Grimm, M. J., Vethanayagam, R. R., Almyroudis, N. G., Dennis, C. G., Khan, A. N. H., D’Auria, A. C., Singel, K. L., Davidson, B. A., Knight, P. R., Blackwell, T. S., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202800 · Cited by 81 · see citing works
Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses
Lesbats, J., Brillac, A., Reisz, J. A., Mukherjee, P., Lhuissier, C., Fernández-Monreal, M., Dupuy, J.-W., Sequeira, A., Tioli, G., De La Calle Arregui, C., et al. (2025) · Nature · doi:10.1038/s41586-025-08629-4 · Cited by 74 · see citing works
STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment
Frisch, J., Angenendt, A., Hoth, M., Prates Roma, L., & Lis, A. (2019) · Cancers · doi:10.3390/cancers11040457 · Cited by 68 · see citing works
Macrophages in nonalcoholic fatty liver disease: a role model of pathogenic immunometabolism
Krenkel, O., & Tacke, F. (2017) · Seminars in Liver Disease · doi:10.1055/s-0037-1604480 · Cited by 66 · see citing works
Macrophages in metabolic associated fatty liver disease
Alharthi, J., Latchoumanin, O., George, J., & Eslam, M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i16.1861 · Cited by 65 · see citing works
Mitochondrial ros potentiates indirect activation of the aim2 inflammasome
Crane, D. D., Bauler, T. J., Wehrly, T. D., & Bosio, C. M. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00438 · Cited by 63 · see citing works
Hypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis
Jantsch, J., & Schödel, J. (2015) · Immunobiology · doi:10.1016/j.imbio.2014.09.009 · Cited by 46 · see citing works
A Perspective on the Role of Extracellular Hemoglobin on the Innate Immune System
Lee, S. K., & Ding, J. L. (2013) · DNA and Cell Biology · doi:10.1089/dna.2012.1897 · Cited by 52 · see citing works
Tian, S., Chen, X., Wu, W., Lin, H., Qing, X., Liu, S., Wang, B., Xiao, Y., Shao, Z., & Peng, Y. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01168-4 · Cited by 53 · see citing works
Abuaita, B. H., Burkholder, K. M., Boles, B. R., & O’Riordan, M. X. (2015) · mBio · doi:10.1128/mbio.00705-15 · Cited by 48 · see citing works
Reprogramming of mitochondrial metabolism by innate immunity
Garaude, J. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.010 · Cited by 33 · see citing works
- Authors
- West, A. P., Brodsky, I. E., Rahner, C., Woo, D. K., Erdjument-Bromage, H., Tempst, P., Walsh, M. C., Choi, Y., Shadel, G. S., & Ghosh, S.
- Affiliations
- Yale University (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Pennsylvania (US)
- Columbia University (US)
- Corresponding author
- Ghosh, Sankar
- ORCID
- Venue
- Nature
- Published
- 2011-04
- Volume
- 472
- Issue
- 7344
- Pages
- 476-480
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3460538
- OpenAlex
- W1977039417
- Cited by
- 1,659
- References
- 37
- Citations by year
- 2026: 112 · 2025: 116 · 2024: 137 · 2023: 132 · 2022: 129 · 2021: 160 · 2020: 145 · 2019: 108 · 2018: 97 · 2017: 104 · 2016: 94 · 2015: 85 · 2014: 75 · 2013: 74 · 2012: 67
- FWCI
- 33.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R37 AI33443, R37AI033443, R01AI033443)
- National Institute of Neurological Disorders and Stroke (NS-056206, R01NS056206)
- National Institute of Environmental Health Sciences (P01ES011163)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Toll-like receptors, TLR1, TLR2, TLR4, macrophages, mitochondrial reactive oxygen species, bactericidal activity, phagosome, TRAF6, ECSIT, ubiquitination, mitochondrial recruitment, intracellular bacterial killing, catalase, innate immune signaling, mitochondria
- MeSH terms
- Animals, Catalase, Cell Line, Immunity, Innate, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Phagosomes, Salmonella, Signal Transduction, Reactive Oxygen Species, Ubiquitin-Protein Ligases, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Mice, Ubiquitination
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