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Kidney Week

Abstract: FR-PO362

Apolipoprotein C3 Induces Systemic Inflammation and Organ Damage in CKD by Alternative Inflammasome Activation via a Novel Pathway

Session Information

  • CKD: Mechanisms - II
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Speer, Thimoteus, Saarland University Hospital, Homburg/Saar, Germany
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Schunk, Stefan J., Saarland University Hospital, Homburg/Saar, Germany
  • Fliser, Danilo, Saarland University Hospital, Homburg/Saar, Germany
  • Zewinger, Stephen, Saarland University Hospital, Homburg/Saar, Germany
Background

CKD is associated with systemic sterile inflammation promoting the progression of CKD. Activation of the NLRP3 inflammasome plays an important role by inducing the release of the key alarminin Interleukin-1β (IL-1β). Identification of endogenous inflammasome activators in CKD patients is essential for the development of new anti-inflammatory treatment strategies.

Methods

Lipoproteins from CKD patients were fractioned. Their effect on IL-1b release was determined in human monocytes and in murine macrophages. Mechanistically, the NLRP3 activation by lipoproteins was studied in detail in vitro and several murine models. The relevance of these findings was studied in humanized mice subjected to unilateral ureter obstruction (UUO) or carotid perivascular injury.

Results

The VLDL fraction of lipoproteins from CKD patients substantially stimulated IL-1β release from human monocytes. Using proteomics, we found apolipoprotein-C3 (ApoC3) to accumulate within VLDL from CKD patients. ApoC3 stimulated pro-inflammatory activation of human monocytes in vitro and promoted a pro-inflammatory state in vivo in mice with accumulation of macrophages within the kidneys. Mechanistically, ApoC3 activated the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptor-2/4 leading to alternative inflammasome activation, a novel and previously unknown pathway. In general, we found that alternative inflammasome activation in human monocytes is mediated by Toll-like receptor adapter protein SCIMP. In humanized mice, ApoC3 activated human monocytes to impede endothelial regeneration and to substantially promote kidney injury. ApoC3 plasma levels were increased in patients with incipient CKD and associated with higher mortality in a large clinical trial (N=3,313) of patients undergoing coronary angiography after a median follow-up of 9.9 years.

Conclusion

These data provide novel insights into the regulation of the NLRP3 inflammasome activation in general and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3 in the progression of CKD and in CKD-associated cardiovascular disease. Targeting ApoC3 has the potential to prevent kidney damage and to provide an anti-inflammatory treatment strategy in patients with CKD.