Regulation of Phagosome Maturation by Signals from Toll-Like Receptors
Abstract
In higher metazoans, phagocytosis is essential in host defense against microbial pathogens and in clearance of apoptotic cells. Both microbial and apoptotic cells are delivered on a common route from phagosomes to lysosomes for degradation. Here, we found that activation of the Toll-like receptor (TLR) signaling pathway by bacteria, but not apoptotic cells, regulated phagocytosis at multiple steps including internalization and phagosome maturation. Phagocytosis of bacteria was impaired in the absence of TLR signaling. Two modes of phagosome maturation were observed, constitutive and inducible; their differential engagement depended on the ability of the cargo to trigger TLR signaling.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The discovery of selective activation of Dectin-1/Syk signaling during germination of Aspergillus conidia due to stage-specific surface exposure of β-glucan and the ability of PRR to regulate phagosome maturation provided the conceptual framework of PAMPs masking as a mechanism employed by fungi to escape macrophage killing.
“The discovery of selective activation of Dectin-1/Syk signaling during germination of Aspergillus conidia due to stage-specific surface exposure of β-glucan (194, 246, 247) and the ability of PRR to regulate phagosome maturation (248) provided the conceptual framework of pathogen-associated molecular patterns (PAMPs) masking as a mechanism employed by fungi to escape macrophage killing.”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [248]
Cites
Takeda, K., Kaisho, T., & Akira, S. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141126 · Cited by 6,143 · see citing works
Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80119-3 · Cited by 3,680 · see citing works
Mechanisms of phagocytosis in macrophages
Aderem, A., & Underhill, D. M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.593 · Cited by 2,854 · see citing works
Mellman, I., & Steinman, R. M. (2001) · Cell · doi:10.1016/s0092-8674(01)00449-4 · Cited by 2,256 · see citing works
Kornfeld, S. A., & Mellman, I. (1989) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.05.110189.002411 · Cited by 1,593 · 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
Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases
Caron, E., & Hall, A. (1998) · Science · doi:10.1126/science.282.5394.1717 · Cited by 1,019 · see citing works
Activation of Lysosomal Function During Dendritic Cell Maturation
Trombetta, E. S., Ebersold, M. W., Garrett, W. S., Pypaert, M., & Mellman, I. (2003) · Science · doi:10.1126/science.1080106 · Cited by 740 · see citing works
Phagosome maturation: aging gracefully
Vieira, O. V., Botelho, R. J., & Grinstein, S. (2002) · Biochemical Journal · doi:10.1042/bj20020691 · Cited by 675 · see citing works
Membrane transport in the endocytic pathway
Gruenberg, J. E., & Maxfield, F. R. (1995) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(95)80013-1 · Cited by 645 · see citing works
Phagocytosis and innate immunity
Greenberg, S., & Grinstein, S. (2002) · Current Opinion in Immunology · doi:10.1016/s0952-7915(01)00309-0 · Cited by 581 · see citing works
Rab GTPases: specifying and deciphering organelle identity and function
Pfeffer, S. R. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02147-x · Cited by 528 · see citing works
Henson, P. M., Bratton, D. L., & Fadok, V. A. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00474-2 · Cited by 485 · see citing works
Effects of cytokines on mycobacterial phagosome maturation
Via, L. E., Fratti, R. A., McFalone, M., Pagán-Ramos, E., Deretic, D., & Deretic, V. P. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.7.897 · Cited by 354 · see citing works
The phosphatidylserine receptor: a crucial molecular switch?
Henson, P. M., Bratton, D. L., & Fadok, V. A. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35085094 · Cited by 321 · see citing works
Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens
Rosenberger, C. M., & Finlay, B. B. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1104 · Cited by 300 · see citing works
The Stress-Induced MAP Kinase p38 Regulates Endocytic Trafficking via the GDI:Rab5 Complex
Cavalli, V., Vilbois, F., Felberbaum‐Corti, M., Marcote, M. J., Tamura, K., Karin, M., Arkinstall, S., & Gruenberg, J. E. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00189-7 · Cited by 288 · see citing works
Immunity in infective diseases
Metchnikoff, É., & Binnie, F. G. (1905) · University Press eBooks · doi:10.5962/bhl.title.29861 · Cited by 266 · see citing works
Characterization and cloning of lgp110, a lysosomal membrane glycoprotein from mouse and rat cells.
Granger, B. L., Green, S. A., Gabel, C. A., Howe, C. L., Mellman, I., & Helenius, A. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38504-7 · Cited by 157 · see citing works
The biogenesis of lysosomes: Is it a kiss and run, continuous fusion and fission process?
Storrie, B., & Desjardins, M. (1996) · BioEssays · doi:10.1002/bies.950181108 · Cited by 152 · see citing works
Valhmu, W. B., & Raia, F. J. (2002) · Biochemical Journal · doi:10.1042/0264-6021:3610689 · Cited by 137 · see citing works
Howe, C. L., Granger, B. L., Hull, M. J., et al. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.20.7577 · Cited by 120 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Toll-like receptors in innate immunity
Takeda, K. (2004) · International Immunology · doi:10.1093/intimm/dxh186 · Cited by 3,328 · see citing works
Tlr signalling augments macrophage bactericidal activity through mitochondrial ros
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. (2011) · Nature · doi:10.1038/nature09973 · Cited by 1,659 · see citing works
Aspergillus fumigatus and Aspergillosis in 2019
Latgé, J.-P., & Chamilos, G. (2019) · Clinical Microbiology Reviews · doi:10.1128/cmr.00140-18 · Cited by 1,400 · see citing works
Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Sanjuan, M. A., Dillon, C. P., Tait, S. W. G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., et al. (2007) · Nature · doi:10.1038/nature06421 · Cited by 1,347 · see citing works
The ins and outs of MHC class II-mediated antigen processing and presentation
Roche, P. A., & Furuta, K. (2015) · Nature reviews. Immunology · doi:10.1038/nri3818 · Cited by 1,207 · see citing works
Dectin-1: a signalling non-TLR pattern-recognition receptor
Brown, G. D. (2006) · Nature Reviews Immunology · doi:10.1038/nri1745 · Cited by 1,158 · see citing works
Takahashi, K., Rochford, C. D. P., & Neumann, H. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041611 · Cited by 1,124 · see citing works
Stuart, L. M., & Ezekowitz, R. A. B. (2005) · Immunity · doi:10.1016/j.immuni.2005.05.002 · Cited by 667 · see citing works
The phagosome: compartment with a license to kill
Haas, A. (2007) · Traffic · doi:10.1111/j.1600-0854.2006.00531.x · Cited by 450 · see citing works
TLR-Activated B Cells Suppress T Cell-Mediated Autoimmunity
Lampropoulou, V., Hoehlig, K., Roch, T., Neves, P., Gómez, E. C., Sweenie, C. H., Hao, Y., Freitas, A. A., Steinhoff, U., Anderton, S. M., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.7.4763 · Cited by 436 · see citing works
“TLR stimulation increases the phagocytic activity of macrophages and promotes phagosome maturation, allowing efficient capture and destruction of microbes (14).”
BackgroundClearance of apoptotic cells by phagocytes
Erwig, L.-P., & Henson, P. M. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402184 · Cited by 422 · see citing works
Liu‐Bryan, R., Scott, P., Sydlaske, A., Rose, D. M., & Terkeltaub, R. (2005) · Arthritis & Rheumatism · doi:10.1002/art.21238 · Cited by 414 · see citing works
Bacterial outer membrane vesicles as a platform for biomedical applications: An update
Li, M., Zhou, H., Yang, C., Wu, Y., Zhou, X., Liu, H., & Wang, Y. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.04.031 · Cited by 370 · see citing works
PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance
Mukundan, L., Odegaard, J. I., Morel, C. R., Heredia, J. E., Mwangi, J. W., Ricardo-Gonzalez, R. R., Goh, Y. P. S., Eagle, A. R., Dunn, S. E., Awakuni, J. U. H., et al. (2009) · Nature Medicine · doi:10.1038/nm.2048 · Cited by 368 · see citing works
Human milk: a source of more life than we imagine
Jeurink, P. V., van Bergenhenegouwen, J., Jiménez, E., Knippels, L. M. J., Fernández, L., Garssen, J., Knol, J., Rodríguez, J. M., & Martín, R. (2013) · Beneficial Microbes · doi:10.3920/bm2012.0040 · Cited by 354 · see citing works
Immunomodulation and antitumor activity of κ-carrageenan oligosaccharides
YUAN, H., SONG, J., LI, X., LI, N., & DAI, J. (2006) · Cancer Letters · doi:10.1016/j.canlet.2005.11.032 · Cited by 324 · 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
Miksa, M., Komura, H., Wu, R., Shah, K. G., & Wang, P. (2009) · Journal of Immunological Methods · doi:10.1016/j.jim.2008.11.019 · Cited by 320 · see citing works
Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy
Demento, S. L., Eisenbarth, S. C., Foellmer, H. G., Platt, C., Caplan, M. J., Mark Saltzman, W., Mellman, I., Ledizet, M., Fikrig, E., Flavell, R. A., et al. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.03.034 · Cited by 290 · see citing works
A pathway for phagosome maturation during engulfment of apoptotic cells
Kinchen, J. M., Doukoumetzidis, K., Almendinger, J., Stergiou, L., Tosello-Trampont, A., Sifri, C. D., Hengartner, M. O., & Ravichandran, K. S. (2008) · Nature Cell Biology · doi:10.1038/ncb1718 · Cited by 284 · see citing works
Latgé, J.-P., Beauvais, A., & Chamilos, G. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-030117-020406 · Cited by 207 · see citing works
Zareparsi, S., Buraczynska, M., Branham, K. E. H., Shah, S., Eng, D., Li, M., Pawar, H., Yashar, B. M., Moroi, S. E., Lichter, P. R., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi154 · Cited by 190 · see citing works
Ip, W. K. E., Sokolovska, A., Charriere, G. M., Boyer, L., Dejardin, S., Cappillino, M. P., Yantosca, L. M., Takahashi, K., Moore, K. J., Lacy-Hulbert, A., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000110 · Cited by 148 · see citing works
Ogden, C. A., Pound, J. D., Batth, B. K., Owens, S., Johannessen, I., Wood, K., & Gregory, C. D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.3015 · Cited by 147 · see citing works
Toll-like receptor signaling in the lysosomal pathways
Sanjuan, M. A., Milasta, S., & Green, D. R. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00732.x · Cited by 137 · see citing works
Bailey, M. T., Engler, H., Powell, N. D., Padgett, D. A., & Sheridan, J. F. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00307.2007 · Cited by 124 · see citing works
Sullivan, J. T., Young, E. F., McCann, J. R., & Braunstein, M. (2012) · Infection and Immunity · doi:10.1128/iai.05987-11 · Cited by 107 · see citing works
An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis
Kong, L., Sun, L., Zhang, H., Liu, Q., Liu, Y., Qin, L., Shi, G., Hu, J.-H., Xu, A., Sun, Y.-P., et al. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2009.06.008 · Cited by 86 · see citing works
Duerr, C. U., Zenk, S. F., Chassin, C., Pott, J., Gütle, D., Hensel, M., & Hornef, M. W. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000567 · Cited by 72 · see citing works
Recruitment of CD63 to <i>Cryptococcus neoformans</i> phagosomes requires acidification
Artavanis-Tsakonas, K., Love, J. C., Ploegh, H. L., & Vyas, J. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607528103 · Cited by 63 · see citing works
Characterisation of Innate Fungal Recognition in the Lung
Faro-Trindade, I., Willment, J. A., Kerrigan, A. M., Redelinghuys, P., Hadebe, S., Reid, D. M., Srinivasan, N., Wainwright, H., Lang, D. M., Steele, C., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035675 · Cited by 55 · see citing works
Lin, Y.-C., Kuo, H.-C., Wang, J.-S., & Lin, W.-W. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102739 · Cited by 46 · see citing works
Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens
Jati, S., & Sen, M. (2020) · Macrophage Activation - Biology and Disease · doi:10.5772/intechopen.86433 · Cited by 4 · see citing works
- Authors
- Blander, J. M., & Medzhitov, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Medzhitov, Ruslan
- Venue
- Science
- Published
- 2004-05-14
- Volume
- 304
- Issue
- 5673
- Pages
- 1014-1018
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2098084836
- Cited by
- 991
- References
- 22
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 7 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 26 · 2019: 38 · 2018: 24 · 2017: 46 · 2016: 39 · 2015: 39 · 2014: 49 · 2013: 42 · 2012: 63
- FWCI
- 28.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI-46688)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- phagosome maturation, Toll-like receptors, Toll-like receptor signaling, phagocytosis, bacterial internalization, efferocytosis, lysosomal degradation, host defense against infection
- MeSH terms
- Animals, Antigens, Differentiation, Bacteria, Enzyme Activation, Enzyme Inhibitors, Escherichia coli, Lysosomes, Macrophages, Membrane Glycoproteins, Phagocytosis, Phagosomes, Receptors, Cell Surface, Receptors, Immunologic, Recombinant Proteins, Salmonella typhimurium, Staphylococcus aureus, Signal Transduction, Microscopy, Immunoelectron, Apoptosis, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Mice, Myeloid Differentiation Factor 88
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
