Acute Loss of Apolipoprotein E Triggers an Autoimmune Response That Accelerates Atherosclerosis

Abstract

Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

“…Therefore, we wished to determine whether there is a conserved immune response to dyslipidemia itself, by characterizing the immune compartment of our two mouse strains by flow cytometry of spleen cells. Analysis of a large cohort of mice at 10 days following tamoxifen administration revealed an approximate 2-fold increase in GC formation in the APOE cKO as previously reported 18 , whereas no significant increase in GC cell numbers could be detected in the D374Y strain relative to controls (Fig5a,b), indicating that hypercholesterolemia alone is not sufficient to induce the formation of GCs at this time point and could rather be due to loss of APOE. The absolute cell numbers of the splenic B1 and B2 cell populations were not affected in either APOE cKO or D374Y mice.…”

“…We have previously shown that inducible loss of APOE in the adult mouse leads to acute hypercholesterolemia 18 . We created a complementary mouse model based on the conditional expression of a human proprotein convertase subtilisin/kexin type 9 gain-of-function variant (hPCSK9 D374Y) inserted into the ROSA26 locus.…”

“…Loss of APOE is known to have multiple effects on the immune system, including the formation of splenic germinal centers (GC) 24,25 resulting in increased atherosclerosis 18,26 . Therefore, we wished to determine whether there is a conserved immune response to dyslipidemia itself, by characterizing the immune compartment of our two mouse strains by flow cytometry of spleen cells.…”

“…We rationalised that acutely transitioning to a state of dyslipidemia would provide a window in which to observe the microscopic and molecular transitions that typify atherosclerosis initiation. To achieve this, we utilized two different mouse models of acute dyslipidemia, an inducible Apoe knockout 18 and a novel model with inducible expression of a human proprotein convertase subtilisin/kexin type 9 (hPCSK9) D374Y gain-of-function variant [19][20][21] . Herein, we challenge the hypothesis that a singular pathway demarcates the onset of atherosclerosis.…”

Cardiotrophin-1 Deficiency Abrogates Atherosclerosis Progression

“…One of the most intriguing findings of the present study is the effect of CT-1 deficiency on the cholesterol levels and atherosclerotic plaque size in Apoe −/− mice in accelerated atherosclerosis. Plasma total cholesterol and LDL levels are highly correlated with the extent of coronary atherosclerosis 33 , while hypercholesterolemia also enhances local and systemic proinflammatory responses 34 . Therefore, the reduction of LDL observed in Apoe −/− ct-1 −/− mice on HCD has two very significant consequences: on the one hand, it directly results in diminished LDL retention in the subendothelial space, leading to less atherosclerotic plaque formation; on the other hand, it indirectly leads to reduced inflammation.…”