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.

Additional Metadata
Persistent URL dx.doi.org/10.1038/s41590-019-0548-1, hdl.handle.net/1765/122832
Journal Nature Immunology
Citation
Zewinger, S. (Stephen), Reiser, J. (Jochen), Jankowski, J.A, Alansary, D. (Dalia), Hahm, E. (Eunsil), Triem, S. (Sarah), … Speer, T. (Thimoteus). (2019). Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nature Immunology. doi:10.1038/s41590-019-0548-1