Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.
Stephen ZewingerJochen ReiserVera JankowskiDalia AlansaryEunsil HahmSarah TriemMira KlugStefan J SchunkDavid SchmitRafael KramannChristina KörbelEmmanuel AmpofoMatthias W LaschkeSimina-Ramona SelejanAnna PaschenTobias HerterSusanne SchusterGünther SilbernagelMartina SesterUrban SesterGunter AßmannRobert BalsGerhard KostnerWilli Jahnen-DechentMichael D MengerLucia RohrerWinfried MärzMichael BöhmJoachim JankowskiManfred KopfEicke LatzBarbara A NiemeyerDanilo FliserUlrich LaufsThimoteus SpeerPublished in: Nature immunology (2019)
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.
Keyphrases
- nlrp inflammasome
- endothelial cells
- toll like receptor
- oxidative stress
- anti inflammatory
- cell death
- reactive oxygen species
- pluripotent stem cells
- stem cells
- peripheral blood
- inflammatory response
- mouse model
- immune response
- nuclear factor
- cancer therapy
- drug delivery
- signaling pathway
- data analysis
- replacement therapy
- protein protein