Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation


NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: ApoC3 induces systemic inflammation.
Fig. 2: ApoC3 induces alternative NLRP3 inflammasome activation.
Fig. 3: ApoC3 induces heterodimerization of TLR2 and TLR4.
Fig. 4: Alternative inflammasome activation requires calcium-dependent production of superoxide.
Fig. 5: Alternative inflammasome activation involves the adaptor protein SCIMP.
Fig. 6: ApoC3 and human monocytes induce organ damage in vivo.
Fig. 7: ApoC3 is associated with increased mortality.

Data availability

All original data are available from the corresponding author upon request. Source data for Figs. 1–5 and Supplementary Figs. 1 and 3–5 are provided with the paper.


  1. 1.

    Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nat. Immunol. 12, 204–212 (2011).

    CAS  PubMed  Google Scholar 

  2. 2.

    Broderick, L., De Nardo, D., Franklin, B. S., Hoffman, H. M. & Latz, E. The inflammasomes and autoinflammatory syndromes. Annu. Rev. Pathol. 10, 395–424 (2015).

    CAS  Google Scholar 

  3. 3.

    Leemans, J. C., Kors, L., Anders, H. J. & Florquin, S. Pattern recognition receptors and the inflammasome in kidney disease. Nat. Rev. Nephrol. 10, 398–414 (2014).

    CAS  PubMed  Google Scholar 

  4. 4.

    Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Man, S. M. & Kanneganti, T. D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol. 16, 7–21 (2016).

    CAS  PubMed  Google Scholar 

  7. 7.

    Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).

    CAS  PubMed  Google Scholar 

  8. 8.

    Yang, Y., Wang, H., Kouadir, M., Song, H. & Shi, F. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 10, 128 (2019).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  11. 11.

    Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).

    CAS  PubMed  Google Scholar 

  12. 12.

    Lepedda, A. J. et al. Proteomic analysis of plasma-purified VLDL, LDL, and HDL fractions from atherosclerotic patients undergoing carotid endarterectomy: identification of serum amyloid A as a potential marker. Oxid. Med Cell Longev. 2013, 385214 (2013).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Shridas, P., De Beer, M. C. & Webb, N. R. High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species generation and NLRP3 inflammasome activation. J. Biol. Chem. 293, 13257–13269 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Westerterp, M. et al. Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 25, 1294–1304.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Juntti-Berggren, L. et al. Apolipoprotein CIII promotes Ca2+-dependent β cell death in type 1 diabetes. Proc. Natl Acad. Sci. USA 101, 10090–10094 (2004).

    CAS  PubMed  Google Scholar 

  16. 16.

    Zheng, C. et al. Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion. Eur. Heart J. 34, 615–624 (2013).

    CAS  PubMed  Google Scholar 

  17. 17.

    Gaidt, M. M. et al. Human monocytes engage an alternative inflammasome pathway. Immunity 44, 833–846 (2016).

    CAS  PubMed  Google Scholar 

  18. 18.

    Tseng, H. H., Vong, C. T., Kwan, Y. W., Lee, S. M. & Hoi, M. P. TRPM2 regulates TXNIP-mediated NLRP3 inflammasome activation via interaction with p47 phox under high glucose in human monocytic cells. Sci. Rep. 6, 35016 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    CAS  PubMed  Google Scholar 

  20. 20.

    Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Gross, O. et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009).

    CAS  PubMed  Google Scholar 

  22. 22.

    Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010).

    CAS  PubMed  Google Scholar 

  23. 23.

    Hara, H. et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 14, 1247–1255 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Rolli, V. et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol. Cell 10, 1057–1069 (2002).

    CAS  PubMed  Google Scholar 

  25. 25.

    Luo, L. et al. SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. Nat. Commun. 8, 14133 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Hahm, E. et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat. Med. 23, 100–106 (2017).

    CAS  PubMed  Google Scholar 

  27. 27.

    Zewinger, S. et al. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol. 5, 534–543 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Jin, M. S. & Lee, J. O. Structures of the Toll-like receptor family and its ligand complexes. Immunity 29, 182–191 (2008).

    CAS  PubMed  Google Scholar 

  29. 29.

    Kang, J. Y. et al. Recognition of lipopeptide patterns by Toll-like receptor 2–Toll-like receptor 6 heterodimer. Immunity 31, 873–884 (2009).

    CAS  PubMed  Google Scholar 

  30. 30.

    Jin, M. S. et al. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130, 1071–1082 (2007).

    CAS  PubMed  Google Scholar 

  31. 31.

    Lee, H. K., Dunzendorfer, S. & Tobias, P. S. Cytoplasmic domain-mediated dimerizations of Toll-like receptor 4 observed by β-lactamase enzyme fragment complementation. J. Biol. Chem. 279, 10564–10574 (2004).

    CAS  PubMed  Google Scholar 

  32. 32.

    Latz, E. et al. Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat. Immunol. 8, 772–779 (2007).

    CAS  PubMed  Google Scholar 

  33. 33.

    Liu, T. et al. Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. Cell Rep. 8, 974–982 (2014).

    CAS  PubMed  Google Scholar 

  34. 34.

    Kralova, J. et al. The transmembrane adaptor protein SCIMP facilitates sustained dectin-1 signaling in dendritic cells. J. Biol. Chem. 291, 16530–16540 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Amoui, M., Draberova, L., Tolar, P. & Draber, P. Direct interaction of Syk and Lyn protein tyrosine kinases in rat basophilic leukemia cells activated via type I Fc epsilon receptors. Eur. J. Immunol. 27, 321–328 (1997).

    CAS  PubMed  Google Scholar 

  36. 36.

    Katsnelson, M. A., Rucker, L. G., Russo, H. M. & Dubyak, G. R. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J. Immunol. 194, 3937–3952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gimbrone, M. A. Jr & Garcia-Cardena, G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ. Res. 118, 620–636 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Pollin, T. I. et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322, 1702–1705 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Jorgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).

    PubMed  Google Scholar 

  40. 40.

    TG and HDL Working Group of the Exome Sequencing Projectet al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).

    Google Scholar 

  41. 41.

    Saleheen, D. et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544, 235–239 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Khetarpal, S. A. et al. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat. Med. 23, 1086–1094 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Wyler von Ballmoos, M. C., Haring, B. & Sacks, F. M. The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis. J. Clin. Lipidol. 9, 498–510 (2015).

    PubMed  Google Scholar 

  44. 44.

    Gaudet, D. et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015).

    CAS  PubMed  Google Scholar 

  45. 45.

    Freigang, S. et al. Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat. Immunol. 14, 1045–1053 (2013).

    CAS  PubMed  Google Scholar 

  46. 46.

    KDIGO. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 3, 1–150 (2013).

  47. 47.

    Winkelmann, B. R. et al. Rationale and design of the LURIC study—a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2, S1–S73 (2001).

    CAS  PubMed  Google Scholar 

  48. 48.

    Fredenrich, A. et al. Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions. J. Lipid Res. 38, 1421–1432 (1997).

    CAS  PubMed  Google Scholar 

  49. 49.

    Shroff, R. et al. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. J. Am. Soc. Nephrol. 25, 2658–2668 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Zewinger, S. et al. Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. Eur. Heart J. 36, 3007–3016 (2015).

    CAS  PubMed  Google Scholar 

  51. 51.

    Zewinger, S. et al. HDL cholesterol is not associated with lower mortality in patients with kidney dysfunction. J. Am. Soc. Nephrol. 25, 1073–1082 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Wessel, D. & Flugge, U. I. A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal. Biochem. 138, 141–143 (1984).

    CAS  PubMed  Google Scholar 

  53. 53.

    Steyrer, E. & Kostner, G. M. Activation of lecithin-cholesterol acyltransferase by apolipoprotein D: comparison of proteoliposomes containing apolipoprotein D, A-I or C-I. Biochim. Biophys. Acta 958, 484–491 (1988).

    CAS  PubMed  Google Scholar 

  54. 54.

    Jankowski, V. et al. The enzymatic activity of the VEGFR2 receptor for the biosynthesis of dinucleoside polyphosphates. J. Mol. Med. (Berl.) 91, 1095–1107 (2013).

    CAS  Google Scholar 

Download references


This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB/TRR 219), Else-Kröener Fresenius Foundation, Deutsche Nierenstiftung and European Uremic Toxin Work Group of the ERA-EDTA. This study was supported by funding from the European Community’s program ‘European Regional Development Fund Interreg’ to ‘EURIPIDS’ and the Deutsche Forschungsgemeinschaft (SFB894 A2, SFB1027 C4 and SFB TRR 219).

Author information




S.Z., D.F., U.L. and T.S. conceived of the study idea. S.Z., J.R., E.H., V.J., G.K., C.K., B.A.N., L.R., D.F., U.L. and T.S. designed the methodology. S.Z., W.M. and T.S. performed the formal analysis. S.Z., V.J., G.K., D.A., D.S., S.J.S., R.K., E.A., M.Klug, S.T., C.K., S.-R.S., G.A., R.B., A.P., T.H., B.A.N. and T.S. performed the investigation. W.M., J.J., C.K., M.Kopf, G.K., M.W.L., M.D.M. and B.A.N. provided resources. S.Z., D.F., U.L. and T.S. wrote the original draft of the manuscript. J.R., E.H., V.J., G.K., D.A., D.S., S.J.S., R.K., E.A., C.K., S.-R.S., S.S., G.S., M.S., U.S., W.J.-D., L.R., G.A., R.B., M.W.L., M.D.M., W.M., M.B., J.J., M.Kopf, E.L. and B.A.N. reviewed and edited the manuscript. S.Z., V.J. and T.S. visualized the results. S.Z., D.F., U.L. and T.S. acquired funding and supervised the research.

Corresponding author

Correspondence to Thimoteus Speer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1

ApoC3 induces alternative NLRP3 inflammasome activation in human monocytes.

Extended Data Fig. 2

ApoC3 induces TLR-dependent effector responses.

Extended Data Fig. 3

TLR2 and TLR4 mediate activation of human monocytes in response to ApoC3.

Extended Data Fig. 4

TRPM2 is required to mediate alternative inflammasome activation.

Extended Data Fig. 5

ApoC3 induces phosphorylation of Syk downstream of Trif.

Extended Data Fig. 6

Summary on the mechanisms leading to alternative inflammasome activation in human monocytes by ApoC3.

Extended Data Fig. 7

Characterization of the humanized mouse models.

Extended Data Fig. 8

Histological changes in humanized mice after unilateral ureter ligation.

Supplementary information

Supplementary Information

Supplementary Tables 1–4 and Figs. 1–8


Reporting Summary

Source data

Source Data Fig. 1

Unprocessed Western Blots

Source Data Fig. 2

Unprocessed Western Blots

Source Data Fig. 3

Unprocessed Western Blots

Source Data Fig. 4

Unprocessed Western Blots

Source Data Fig. 5

Unprocessed Western Blots

Source Data Extended Data Fig. 1

Unprocessed Western Blots

Source Data Extended Data Fig. 3

Unprocessed Western Blots

Source Data Extended Data Fig. 4

Unprocessed Western Blots

Source Data Extended Data Fig. 5

Unprocessed Western Blots

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zewinger, S., Reiser, J., Jankowski, V. et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat Immunol 21, 30–41 (2020).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing