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Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

Abstract

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.

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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.

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Acknowledgements

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).

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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.

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Correspondence to Thimoteus Speer.

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The authors declare no competing interests.

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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.

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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

41590_2019_548_MOESM2_ESM.pdf

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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). https://doi.org/10.1038/s41590-019-0548-1

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