In her PhD thesis, Marina Sokolova has looked at the role of the NLRP3 inflammasome in obesity-related remodelling and dysfunction of the heart.

MAIN RESULTS:

1. Palmitate activates NLRP3 in cardiac fibroblasts.
2. Mice without NLRP3 escape diabetes induced by oxidative stress because of preserved pancreatic β-cell function.
3. Inhibition of NLRP3 reduces obesity-related cardiac remodelling and dysfunction.

THESIS DEFENCE:

Thesis: Pathogenic consequences of NLRP3 inflammasome activation in metabolic disturbances
Candidate: Marina Sokolova
Time: October 18, 2018 at 12:15
Place: University of Oslo, Domus Medica: Runde auditorium R-105
Link to university website (in Norwegian)

SUMMARY:

When activated, the NLRP3 inflammasome activates the highly inflammatory cytokines interleukin-1β and interleukin-18. The inflammatory process plays an important role in the pathophysiology of metabolic disease, including cardiovascular diseases.

(1) The saturated fatty acid palmitate can activate NLRP3 and trigger inflammatory responses in cardiac fibroblast. Activated fibroblasts induce cardiac hypertrophy and fibrosis. Palmitate does not activate NLRP3 on its own, and activation was only present in lipopolysaccharide-primed cells.

The study includes experiments with wild type mice and mice lacking the NLRP3 or ASC component of the NLRP3 inflammasome. The immune receptor TLR4 was also activated in cells stimulated with palmitate, leading to production of the inflammatory TNF, interleukin-6 and CXCL2 molecules.

(2) Inhibition of the NLRP3 inflammasome can protect β-cells in the pancreativ islets and potentially prevent diabetes, according to Sokolowa’s research. Mice lacking NLRP3 have sustained pacreatic islet function during oxidative stress compared to wild type mice, and are less likely to get diabetes.

(3) Furthermore, a currently unpublished article shows that NLP3 inflammasome inhibition leads to markedly reduced obesity-related cardiac remodelling and dysfunction.

REFERENCES:

(1) Sokolova, M., Vinge, L. E., Alfsnes, K., Olsen, M. B., Eide, L., Kaasbøll, O. J., Attramadal, H., Torp, M-K., Fosshaug, L. E., Rashidi, A., Lien, E., Finsen, A. V., Sandanger, Ø, Aukrust, P., Ranheim, T., & Yndestad, A. (2017). Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1862(2), 234-245.

(2) Sokolova, M., Sahraoui, A., Høyem, M., Øgaard, J., Lien, E., Aukrust, P., Yndestad, A., Ranheim, T.,  & Scholz, H. (2018). NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. American Journal of Physiology-Endocrinology and Metabolism.