Complement membrane attack complexes assemble NLRP3 inflammasomes triggering IL-1 activation of IFN-γ–primed human endothelium
Open accessAbstract
Rationale: Complement activation contributes to multiple immune-mediated pathologies. In late allograft failure, donor-specific antibody deposits complement membrane attack complexes (MAC) on graft endothelial cells (ECs), substantially increasing their immunogenicity without causing lysis. Internalized MAC stabilize NIK (NF-κB [nuclear factor kappa-light-chain-enhancer of activated B cells]–inducing kinase) protein on Rab5+MAC+ endosomes, activating noncanonical NF-κB signaling. However, the link to increased immunogenicity is unclear. Objective: To identify mechanisms by which alloantibody and internalized MAC activate ECs to enhance their ability to increase T-cell responses. Methods and Results: In human EC cultures, internalized MAC also causes NLRP3 (NOD-like receptor family pyrin domain containing 3) translocation from endoplasmic reticulum to Rab5+MAC+NIK+ endosomes followed by endosomal NIK-dependent inflammasome assembly. Cytosolic NIK, stabilized by LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells), does not trigger inflammasome assembly, and ATP-triggered inflammasome assembly does not require NIK. IFN-γ (interferon-γ) primes EC responsiveness to MAC by increasing NLRP3, pro-caspase 1, and gasdermin D expression. NIK-activated noncanonical NF-κB signaling induces pro-IL (interleukin)-1β expression. Inflammasome processed pro-IL-1β, and gasdermin D results in IL-1β secretion that increases EC immunogenicity through IL-1 receptor signaling. Activation of human ECs lining human coronary artery grafts in immunodeficient mouse hosts by alloantibody and complement similarly depends on assembly of an NLRP3 inflammasome. Finally, in renal allograft biopsies showing chronic rejection, caspase-1 is activated in C4d + ECs of interstitial microvessels, supporting the relevance of the cell culture findings. Conclusions: In response to antibody-mediated complement activation, IFN-γ-primed human ECs internalize MAC, triggering both endosomal-associated NIK-dependent NLRP3 inflammasome assembly and IL-1 synthesis, resulting in autocrine/paracrine IL-1β-mediated increases in EC immunogenicity. Similar responses may underlie other complement-mediated pathologies.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
MAC recruits and activates leukocytes by coordinating inflammasome activation and endothelial cytokine signalling.
“It has also been shown that MAC recruits and activates leukocytes by coordinating inflammasome activation and endothelial cytokine signalling [196,197,198,199,200]”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [197]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., Wang, F., & Shao, F. (2015) · Nature · doi:10.1038/nature15514 · Cited by 6,659 · see citing works
A role for mitochondria in nlrp3 inflammasome activation
Zhou, R., Yazdi, A. S., Menu, P., & Tschopp, J. (2011) · Nature · doi:10.1038/nature09663 · Cited by 5,602 · see citing works
Schroder, K., & Tschopp, J. (2010) · Cell · doi:10.1016/j.cell.2010.01.040 · Cited by 5,475 · see citing works
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Coll, R. C., Robertson, A. A. B., Chae, J. J., Higgins, S. C., Muñoz-Planillo, R., Inserra, M. C., Vetter, I., Dungan, L. S., Monks, B. G., Stutz, A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3806 · Cited by 2,849 · see citing works
Mechanism and Regulation of NLRP3 Inflammasome Activation
He, Y., Hara, H., & Núñez, G. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.09.002 · Cited by 2,759 · see citing works
Muñoz-Planillo, R., Kuffa, P., Martínez-Colón, G. J., Smith, B. L., Rajendiran, T. M., & Núñez, G. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.016 · Cited by 2,167 · see citing works
Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D., & Maniatis, T. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.10.7542214 · Cited by 1,718 · see citing works
The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages
Evavold, C. L., Ruan, J., Tan, Y., Xia, S., Wu, H., & Kagan, J. C. (2018) · Immunity · doi:10.1016/j.immuni.2017.11.013 · Cited by 1,115 · see citing works
Complement-Binding Anti-HLA Antibodies and Kidney-Allograft Survival
Loupy, A., Lefaucheur, C., Vernerey, D., Prugger, C., Huyen, J. D. V., Mooney, N., Suberbielle, C., Frémeaux‐Bacchi, V., Méjean, A., Desgrandchamps, F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302506 · Cited by 854 · see citing works
Gurcel, L., Abrami, L., Girardin, S. E., Tschopp, J., & van der Goot, F. G. (2006) · Cell · doi:10.1016/j.cell.2006.07.033 · Cited by 508 · see citing works
The inflammasomes: mechanisms of activation and function
Latz, E. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.12.004 · Cited by 455 · see citing works
T cell migration in rheumatoid arthritis
Mellado, M. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00384 · Cited by 291 · see citing works
The complement system in systemic lupus erythematosus: an update
Leffler, J., Bengtsson, A. A., & Blom, A. M. (2014) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2014-205287 · Cited by 265 · see citing works
The complement system as a potential therapeutic target in rheumatic disease
Trouw, L. A., Pickering, M. C., & Blom, A. M. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.125 · Cited by 216 · see citing works
Carman, C. V., & Martinelli, R. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00603 · Cited by 208 · see citing works
Denk, A., Goebeler, M., Schmid, S., Berberich, I., Ritz, O., Lindemann, D., Ludwig, S., & Wirth, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102698200 · Cited by 204 · see citing works
Participation of blood vessel cells in human adaptive immune responses
Pober, J. S., & Tellides, G. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.09.006 · Cited by 149 · see citing works
Self-citationJane-wit, D., Manes, T. D., Yi, T., Qin, L., Clark, P., Kirkiles-Smith, N. C., Abrahimi, P., Devalliere, J., Moeckel, G., Kulkarni, S., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.002972 · Cited by 144 · see citing works
Self-citationMannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo
McMullen, M. E., Hart, M. L., Walsh, M. C., et al. (2006) · Immunobiology · doi:10.1016/j.imbio.2006.06.011 · Cited by 108 · see citing works
Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin
Busche, M. N., Pavlov, V. I., Takahashi, K., et al. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00049.2009 · Cited by 92 · see citing works
Baylis, R. A., Gomez, D. A., Mallat, Z., Pasterkamp, G., & Owens, G. K. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310097 · Cited by 92 · see citing works
Madge, L. A., Kluger, M. S., Orange, J. S., & May, M. J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.3467 · Cited by 82 · see citing works
B Cell Immunity in Solid Organ Transplantation
Karahan, G. E., Claas, F. H. J., & Heidt, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00686 · Cited by 66 · see citing works
Jane‐wit, D., Surovtseva, Y. V., Qin, L., Li, G., Liu, R., Clark, P. L., Manes, T. D., Wang, C., Kashgarian, M. J., Kirkiles-Smith, N. C., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503535112 · Cited by 64 · see citing works
Self-citationRecent advances in allograft vasculopathy
Merola, J., Jane‐wit, D., & Pober, J. S. (2016) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000370 · Cited by 64 · see citing works
Self-citationKaabak, M. M., Бабенко, Н. Н., Shapiro, R., Zokoev, A. K., Dymova, O. V., & Kim, E. J.-H. (2018) · Pediatric Transplantation · doi:10.1111/petr.13129 · Cited by 64 · see citing works
Blood Vessels in Allotransplantation
Abrahimi, P., Liu, R. J., & Pober, J. S. (2015) · American Journal of Transplantation · doi:10.1111/ajt.13242 · Cited by 62 · see citing works
Self-citationThe Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice
Cross, A. R., Glotz, D., & Mooney, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00106 · Cited by 60 · see citing works
Danobeitia, J. S., Ziemelis, M., Ma, X., Zitur, L. J., Zens, T. J., Chlebeck, P. J., van Amersfoort, E. S., & Fernandez, L. A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0183701 · Cited by 50 · see citing works
Complement in Kidney Transplantation
Cernoch, M., & Viklický, O. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00066 · Cited by 42 · see citing works
Farrar, C. A., & Sacks, S. H. (2013) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0000000000000037 · Cited by 29 · see citing works
Qin, L., Li, G., Kirkiles-Smith, N. C., et al. (2016) · American Journal of Transplantation · doi:10.1111/ajt.13834 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [13]Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–832 [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
Sun, X., Zhou, R., Lei, Y., Hu, J., & Li, X. (2020) · Brain Research · doi:10.1016/j.brainres.2020.147109 · Cited by 28 · see citing works
- Authors
- Xie, C. B., Qin, L., Li, G., Fang, C., Kirkiles-Smith, N. C., Tellides, G., Pober, J. S., & Jane-wit, D.
- Affiliations
- Yale University (US)
- Division of Cardiovascular Medicine (C.F., D.J.-w), Yale University School of Medicine, New Haven, CT.
- Venue
- Circulation Research
- Published
- 2019-06-07
- Volume
- 124
- Issue
- 12
- Pages
- 1747-1759
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6557295
- OpenAlex
- W2940337896
- Cited by
- 89
- References
- 32
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 11 · 2020: 12 · 2019: 3
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute for Health and Care Research
- National Institutes of Health (UL1TR001863)
- National Heart, Lung, and Blood Institute (R00HL125895, R01HL051014, R01HL141137)
- National Institute of General Medical Sciences (T32GM007205)
- National Institute of Allergy and Infectious Diseases (U01AI132895, F30AI138473)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR053495)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- membrane attack complex, NLRP3 inflammasome, NIK, non-canonical NF-κB signaling, alloantibodies, IFN-γ priming, IL-1β secretion, gasdermin D, caspase-1, chronic rejection, donor-specific antibodies
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Adult, Cells, Cultured, Endothelium, Vascular, Female, Humans, Interferon-gamma, Interleukin-1, Male, Complement Membrane Attack Complex, HEK293 Cells, Inflammasomes, Human Umbilical Vein Endothelial Cells
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
