Abstract
Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gross, O., Thomas, C. J., Guarda, G. & Tschopp, J. The inflammasome: an integrated view. Immunol. Rev. 243, 136–151 (2011).
Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).
Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).
Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell 166, 288–298 (2016).
Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156, 1193–1206 (2014).
Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477 (2014).
Lamkanfi, M. & Dixit, V. M. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol. 28, 137–161 (2012).
Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).
Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).
Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).
Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
Jiang, X. & Wang, X. Cytochrome c-mediated apoptosis. Annu. Rev. Biochem. 73, 87–106 (2004).
Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).
Kang, D., Kim, S. H. & Hamasaki, N. Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 7, 39–44 (2007).
He, Y., Zeng, M. Y., Yang, D., Motro, B. & Núñez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016).
Shi, H. et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258 (2016).
Schmid-Burgk, J. L. et al. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J. Biol. Chem. 291, 103–109 (2016).
Jehl, S. P., Nogueira, C. V., Zhang, X. & Starnbach, M. N. IFNγ inhibits the cytosolic replication of Shigella flexneri via the cytoplasmic RNA sensor RIG-I. PLoS Pathog. 8, e1002809 (2012).
Xu, Y., Johansson, M. & Karlsson, A. Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized in mitochondria. J. Biol. Chem. 283, 1563–1571 (2008).
Milon, L. et al. The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase. J. Biol. Chem. 275, 14264–14272 (2000).
Chen, Y. L., Lin, D. W. & Chang, Z. F. Identification of a putative human mitochondrial thymidine monophosphate kinase associated with monocytic/macrophage terminal differentiation. Genes Cells 13, 679–689 (2008).
Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).
Elliott, E. I. & Sutterwala, F. S. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol. Rev. 265, 35–52 (2015).
West, A. P. et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480 (2011).
Hudson, G. & Chinnery, P. F. Mitochondrial DNA polymerase-gamma and human disease. Hum. Mol. Genet. 15, R244–R252 (2006).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
Ballana, E. & Esté, J. A. SAMHD1: at the crossroads of cell proliferation, immune responses, and virus restriction. Trends Microbiol. 23, 680–692 (2015).
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003).
Zhong, Z. et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat. Commun. 4, 1611 (2013).
Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).
Malik, A. N., Czajka, A. & Cunningham, P. Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences. Mitochondrion 29, 59–64 (2016).
Acknowledgements
We thank eBioscience, Cell Signaling Technologies, Santa Cruz Technologies, and Thermo Fisher for gifts of reagents, and N. Yan and J. Rehwinkel for SAMHD1-deficient murine bone marrow. Z.Z. was supported by Cancer Research Institute (CRI) Irvington Fellowship, Prevent Cancer Foundation Board of Directors Research Fund, and American Association for the Study of Liver Diseases Pinnacle Research Award; F.H. was supported by Eli Lilly LIFA program; S.S. was supported by fellowships from CRI-Irvington and Prostate Cancer Foundation; J.W. was supported by a Canadian Institutes of Health Research fellowship (MFE-135425). Research was supported by NIH grants AI043477 and CA163798 to M.K., AA020172 and DK085252 to E.S., ES010337 to M.K. and E.S., DK109724 and P30DK063491 to A.L.H., DK099205, DK101737 and DK111866 to T.K., AA022614 to T.K. and M.K., Leukemia and Lymphoma Society SCOR grant 20132569 to T. Kipps and M.K., and the Alliance for Lupus Research grant 257214 and CART Foundation to M.K., who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Reviewer information
Nature thanks M. Arditi, M. Murphy and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
Z.Z., S.L. and M.K. conceived the project. Z.Z. and S.L. designed and performed most of the experiments. E.S.-L., F.H., S.S., X-J.L., J.W. and S.D. provided technical assistance. E.S., B.S., A.L.H., T.K. and H.G. provided reagents and research tools. Z.Z., S.L. and M.K. wrote the manuscript with input from all authors.
Corresponding author
Ethics declarations
Competing interests
The University of California San Diego is in the process of applying for a patent application (US Provisional Application Serial no. 62/690,175) covering the use of IRF1 and/or CMPK2 genetic/chemical inhibitors to treat NLRP3 inflammasome-associated diseases that lists Z.Z. and M.K. as inventors.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 TFAM is required for ox-mtDNA generation and NLRP3 inflammasome activation.
a, Inflammasome activator-induced changes in mitochondrial membrane potential (Ψm) in non- or LPS-primed wild-type BMDMs were measured by TMRM fluorescence. Data are mean ± s.d. (n = 3 biological replicates). b, Relative mtROS amounts were measured by MitoSOX fluorescence in non- or LPS-primed wild-type BMDMs after stimulation with different inflammasome activators. Data are mean ± s.d. (n = 3 biological replicates). c, Amounts of 8-OH-dG in mtDNA isolated from the mitochondrial fraction of non- or LPS-primed wild-type BMDMs that were treated with different inflammasome activators. Data are mean ± s.d. (n = 3 biological replicates). d, Cytosolic release of mtDNA, determined by qPCR with primers specific for mtDNA (non-NUMT) and nDNA (B2m), in non- or LPS-primed wild-type BMDMs after treatment with different inflammasome activators. Data are mean ± s.d. (n = 4 biological replicates). e, Immunoblot analysis of TFAM in Tfamf/f and TfamΔMye BMDMs. Results are typical of three independent experiments. f, Relative total mtDNA amounts in Tfamf/f and TfamΔΜye BMDMs determined by qPCR with primers specific for mtDNA (D-loop, non-NUMT) and nDNA (Tert, B2m). Data are mean ± s.d. (n = 3 biological replicates). g, Relative mtROS amounts were measured by MitoSOX fluorescence in LPS-primed Tfamf/f and TfamΔMye BMDMs after stimulation with indicated NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). h, Amounts of 8-OH-dG in mtDNA isolated from the mitochondrial fraction of LPS-primed Tfamf/f and TfamΔMye BMDMs that were stimulated with various NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). i, Immunoblot analysis of Casp1 p20 and mature IL-1β (p17) in culture supernatants of Tfamf/f (W) and TfamΔMye (K) BMDMs that were stimulated with LPS plus different inflammasome activators. Results are typical of three separate experiments. j, Immunoblot analysis of pro-IL-1β, NLRP3, ASC and pro-Casp1 in the lysates of Tfamf/f and TfamΔMye BMDMs before and after LPS priming. Results are typical of three separate experiments. k, l, Amounts of IL-1β (k) and TNF (l) in culture supernatants of LPS-primed Tfamf/f and TfamΔMye BMDMs that were stimulated with various NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). m, Amounts of IL-1β in culture supernatants of LPS-primed Tfamf/f and TfamΔMye BMDMs that were stimulated with H2O2 in the absence and presence of nigericin. Data are mean ± s.d. (n = 3 biological replicates). **P < 0.01; ***P < 0.001; two-sided unpaired t-test.
Extended Data Fig. 2 ox-mtDNA activates the NLRP3 inflammasome.
a, Immunoblot analysis of NLRP3, AIM2 and Polγ in shCtrl- or specific shRNA-transduced BMDMs. Data are typical of three separate experiments. b, Amounts of IL-1β in culture supernatants of LPS-primed TfamΔMye BMDMs that were transfected with mtDNA, methylated mtDNA, ox-mtDNA, and methylated ox-mtDNA. All mtDNAs were 90-bp long and of an identical sequence. Data are mean ± s.d. (n = 3 biological replicates). c, Representative fluorescent microscopy images of wild-type BMDMs that were co-stained for 8-OH-dG, ASC and DAPI before and after stimulation with LPS plus the indicated inflammasome activators. Results are typical of three independent experiments. Scale bars, 5 μm.
Extended Data Fig. 3 LPS induces mtDNA replication.
a, Time-course analysis of total mtDNA amounts in wild-type BMDMs after LPS (200 ng ml−1) stimulation. Data are mean ± s.d. (n = 3 biological replicates). Results are typical of three separate experiments. b, Representative fluorescent microscopy images of EdU-labelled shCtrl- or shPolg-transduced wild-type BMDMs that were stimulated with or without LPS (200 ng ml−1) for 6 h. Scale bars, 5 μm. Results are typical of three separate experiments. c, Percentages of cells with mtDNA replication as determined in b. Data are mean ± s.d. (n = 3 different microscopic fields per group; original magnification, ×40). d, Immunoblot analysis of mitochondrial resident proteins, TOM20 and VDAC, in wild-type BMDMs before and after LPS stimulation. Results are typical of three separate experiments. e, Representative fluorescent microscopy images of the mitochondrial resident protein ATP5B and DAPI staining in wild-type BMDMs before and after LPS stimulation. Results are typical of three independent experiments. Arrows indicate fragmented mitochondria. ***P < 0.001, two-sided unpaired t-test.
Extended Data Fig. 4 MyD88 and TRIF mediate LPS-induced IRF1 and CMPK2 expression and NLRP3 inflammasome activation.
a, Amounts of 8-OH-dG in mtDNA isolated from mitochondrial fractions of wild-type, Myd88−/− and Trif−/− BMDMs that were primed with LPS for different durations followed by stimulation with ATP. Data are mean ± s.d. (n = 3 biological replicates per time point). b, c, Quantification of fluorescent microscopy images of ASC puncta (b) and ASC puncta positive for EdU (c) in wild-type, Myd88−/− and Trif−/− BMDMs that were primed with LPS for different durations, followed by ATP stimulation. Data are mean ± s.d. (n = 3 different microscopic fields per group; original magnification, ×40). d–f, Immunoblot analysis of NLRP3, pro-IL-1β, IRF1 and CMPK2 in wild-type, Myd88−/− and Trif−/− BMDMs before and after LPS stimulation. Data are typical of three separate experiments. *P < 0.05; **P < 0.01; ***P < 0.001; two-sided unpaired t-test.
Extended Data Fig. 5 Effects of IRF1 on priming, mitochondrial damage and non-canonical inflammasome activation.
a, Immunoblot analysis of NLRP3, ASC, pro-caspase-1, pro-IL-1β, NEK7 and IRF1 in the lysates of wild-type and Irf1−/− BMDMs before and after LPS stimulation. Data are typical of three separate experiments. b, Amounts of TNF in culture supernatants of LPS-primed wild-type and Irf1−/− BMDMs that were stimulated with the indicated inflammasome activators. Data are mean ± s.d. (n = 3 biological replicates). c, Percentages of Ψm preservation were measured by TMRM fluorescence in LPS-primed wild-type and Irf1−/− BMDMs that were stimulated with indicated NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). d, Relative amounts of mtROS were measured by MitoSOX fluorescence in LPS-primed wild-type and Irf1−/− BMDMs that were stimulated with indicated NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). e, Immunoblot analysis of caspase-11 and IRF1 in lysates from wild-type and Irf1−/− BMDMs before and after LPS stimulation. Results are typical of three independent experiments. f, Amounts of IL-1β in culture supernatants of LPS-primed wild-type and Irf1−/− BMDMs that were further transfected with FuGENE-complexed LPS. Data are mean ± s.d. (n = 3 biological replicates).
Extended Data Fig. 6 IRF1 mediates LPS-induced CMPK2 expression.
a, Relative amounts of Cmpk2 mRNA in wild-type and Irf1−/− BMDMs before and after LPS stimulation. Data are mean ± s.d. (n = 3 biological replicates per time point). b, Immunoblot analysis of CMPK2, VDAC and tubulin in mitochondrial and cytosolic fractions of wild-type BMDMs after LPS stimulation. Results are typical of three separate experiments. c, Chromatin immunoprecipitation analysis of IRF1 recruitment to the Cmpk2 promoter. Data are mean ± s.d. (n = 4 biological replicates for wild-type and Irf1−/− groups; n = 5 and 6 biological replicates for wild-type + LPS and Irf1−/− + LPS groups, respectively). Cxcl10, a known IRF1-target gene, was included as a positive control. d, Relative mRNA amounts of dGK (also known as Dguok), Tk2, Ak2, Nme4 and Polg in wild-type BMDMs before and after 6 h LPS stimulation. Data are mean ± s.d. (n = 3 biological replicates). e, Immunoblot analysis of the enzymes encoded by the genes in d in the lysates of wild-type BMDMs before and after LPS stimulation. Results are typical of three independent experiments. f, Immunoblot analysis of CMPK2 and NME4 in shCtrl- or specific shRNA-transduced BMDMs. Data are typical of three independent experiments. *P < 0.05; **P < 0.01; two-sided unpaired t-test.
Extended Data Fig. 7 CMPK2 deficiency does not affect inflammasome subunit expression nor NLRP3 activator-induced mitochondrial damage.
a, Immunoblot analysis of pro-IL-1β, NLRP3, ASC, pro-Casp1 and NEK7 in the lysates of wild-type (shCtrl) and CMPK2-deficient (shCmpk2) BMDMs before and after LPS priming. Results are typical of three separate experiments. b, NLRP3 activator-induced changes in Ψm in LPS-primed shCtrl and shCmpk2 BMDMs were measured by TMRM fluorescence. Data are mean ± s.d. (n = 3 biological replicates). c, Relative amounts of mtROS measured by MitoSOX fluorescence in LPS-primed shCtrl and shCmpk2 BMDMs after stimulation with the indicated NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). d, Representative fluorescent microscopy images of EdU-labelled wild-type BMDMs transduced with either shCtrl- or shCmpk2-encoding lentiviruses that were stimulated with or without LPS (200 ng ml−1) for 6 h. Scale bars, 5 μm. e, Percentages of cells with mtDNA replication as determined in d. Data are mean ± s.d. (n = 3 different microscopic fields per group; original magnification, ×40). f, Relative amounts of total mtDNA in wild-type and Irf1−/− BMDMs before and after treatments with the indicated TLR agonists. Data are mean ± s.d. (n = 3 biological replicates). g, Relative amounts of total mtDNA in shCtrl- or shCmpk2-encoding lentivirus-transduced wild-type BMDMs before and after treatments with the indicated TLR agonists. Data are mean ± s.d. (n = 3 biological replicates). *P < 0.05; **P < 0.01; ***P < 0.001; two-sided unpaired t-test.
Extended Data Fig. 8 dNTP availability controls LPS-induced mtDNA synthesis and NLRP3 inflammasome activation.
a, Relative total mtDNA amounts in shCtrl and shNme4 BMDMs before and after LPS priming. Data are mean ± s.d. (n = 3 biological replicates). b, Amounts of 8-OH-dG in mtDNA isolated from the mitochondrial fraction of LPS-primed shCtrl and shNme4 BMDMs that were stimulated with various NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). c, Amounts of 8-OH-dG in cytosolic mtDNA from LPS-primed shCtrl and shNme4 BMDMs that were stimulated with various NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates). d, e, Amounts of IL-1β (d) and TNF (e) in supernatants of LPS-primed shCtrl and shNme4 BMDMs that were stimulated with various inflammasome activators. Data are mean ± s.d. (n = 3 biological replicates). f, Immunoblot analysis of SAMHD1 and Polγ in wild-type and Trif−/− BMDMs that were stimulated with LPS for different durations as indicated. Results are typical of three independent experiments. g, Relative total mtDNA amounts in wild-type and Samhd1−/− BMDMs before and after LPS stimulation. Data are mean ± s.d. (n = 3 biological replicates). h, i, Amounts of IL-1β (h) and TNF (i) in the culture supernatants of LPS-primed wild-type and Samhd1−/− BMDMs that were stimulated with inflammasome activators as indicated. Data are mean ± s.d. (n = 3 biological replicates). j, Amounts of NLRP3 activator-induced IL-1β in culture supernatants of LPS-primed wild-type and Samhd1−/− BMDMs with or without Polg expression. Data are mean ± s.d. (n = 3 biological replicates). *P < 0.05; **P < 0.01; ***P < 0.001; two-sided unpaired t-test.
Extended Data Fig. 9 CMPK2 expression restores NLRP3 inflammasome activation in IRF1-deficient macrophages.
a, Immunoblot analysis of IRF1, CMPK2, pro-IL-1β, NLRP3, ASC and pro-Casp1 in lysates of wild-type and Irf1−/− BMDMs before and after transduction with a wild-type CMPK2-encoding lentivirus. Results are typical of three independent experiments. b, NLRP3 activator-induced changes in Ψm in LPS-primed CMPK2-transduced wild-type and Irf1−/− BMDMs were measured by TMRM fluorescence. Data are mean ± s.d. (n = 3 biological replicates) and analysed by two-sided unpaired t-test (not significant). c, Relative amounts of mtROS measured by MitoSOX fluorescence in LPS-primed control (vector)- or CMPK2-transduced wild-type and Irf1−/− BMDMs before and after stimulation with NLRP3 activators. Data are mean ± s.d. (n = 3 biological replicates) and analysed by two-sided unpaired t-test (not significant). d, Immunoblot analysis of CMPK2 in Irf1−/− BMDMs that were transduced with wild-type or mutant (CMPK2(D330A)) CMPK2-encoding lentiviruses. Results are typical of three separate experiments.
Extended Data Fig. 10 IRF1 is required for in vivo mtDNA replication and NLRP3 inflammasome activation.
a, b, 12-week-old wild-type or Irf1−/− mice were injected intraperitoneally with LPS (50 mg per kg of body weight) and their sera were collected 3 h later and analysed by ELISA for IL-1β (a) and TNF (b). Results are mean ± s.d. (n = 6 and 7 for WT and Irf1−/− mice, respectively). c, Survival of wild-type or Irf1−/− mice that were injected intraperitoneally with LPS (50 mg per kg body weight; n = 10 and 11 for WT and Irf1−/− mice, respectively). d, Relative amounts of total mtDNA in peritoneal infiltrates of wild-type or Irf1−/− mice before and after LPS (50 mg per kg body weight) injection. Data are mean ± s.d. (n = 6 in PBS-treated groups; n = 12 in LPS-treated groups). e, Peritoneal IL-1β in wild-type or Irf1−/− mice 4 h after intraperitoneal injection of alum (1 mg) or PBS. Data are mean ± s.d. (n = 5 in PBS-treated groups; n = 6 in alum-treated groups). f, g, Alum-induced peritoneal infiltration of neutrophils (CD11b+Ly6G+F4/80−) (f) and monocytes (CD11b+Ly6C+Ly6G−) (g) in wild-type and Irf1−/− mice 12 h after alum (1 mg) or PBS injection. Data are mean ± s.e.m. (n = 3 for PBS-treated groups and n = 6 for alum-treated groups). ***P < 0.001; two-sided unpaired t-test (a, b, d–g) and log-rank test (c). h, A working model to illustrate how TLR-mediated priming controls mtDNA replication and NLRP3 inflammasome activation. Whereas IRF1 acts positively to induce the transcription of CMPK2, which supplies rate-limiting dCDP for mtDNA synthesis, TRIF-dependent signalling also acts negatively to limit dNTP supply through the induction of SAMHD1.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1 and 2.
Source Data
Rights and permissions
About this article
Cite this article
Zhong, Z., Liang, S., Sanchez-Lopez, E. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018). https://doi.org/10.1038/s41586-018-0372-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-018-0372-z
This article is cited by
-
Increased expression of NLRP3 associated with elevated levels of HMGB1 in children with febrile seizures: a case–control study
BMC Pediatrics (2024)
-
The involvement of α-synucleinopathy in the disruption of microglial homeostasis contributes to the pathogenesis of Parkinson’s disease
Cell Communication and Signaling (2024)
-
Mechanistic insights from inflammasome structures
Nature Reviews Immunology (2024)
-
Blocking reverse electron transfer-mediated mitochondrial DNA oxidation rescues cells from PANoptosis
Acta Pharmacologica Sinica (2024)
-
Type I Interferon Signalling and Ischemic Stroke: Mechanisms and Therapeutic Potentials
Translational Stroke Research (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
