The immune response to dyslipidemia - Characterization and intervention

AimDyslipidemia-induced tissue damage can provoke broad inflammatory responses, particularly from B cells and macrophages.

We hypothesize that by breaking lipid-homeostasis, we will discover the immune mechanisms that characterize the initiation of atherosclerosis and non-alcoholic fatty liver disease (NAFLD) ImplementationOur approach is based on three novel mouse strains that we have constructed; a conditional knock-out of Apolipoprotein E, an ectopic knock-in of a human PCSK9 and a fluorescent knock-in labelling of Apoliporotein B .Through mRNA-sequencing, we have isolated the transcriptomic signature that defines the response of the Aorta and Liver to acute-dyslipidemia.

This will be expanded to single-cell RNA-seq to identify the phagocytosing cell types that respond to excess and modified lipoproteins, and to ascertain the pro- and anti-inflammatory profiles of these myeloid cells.

Analysis of the immune response in the transition to dyslipidemia revealed the formation of germinal centers and broad humoral responses.

Reintroducing antibodies that neutralize damage-associated molecular patterns will determine the molecular basis of how tissue injury can be prevented by B lymphocyte responses.

SignificanceWe now theorize that inflammation and aortic remodeling defines the primary genesis of atherosclerosis plaque formation, the underlying cause of the most common form of mortality and we provide new targets in potentially ameliorating NALFD.