UCSF

Background and aims

Progranulin is a circulating protein that modulates inflammation and is found in atherosclerotic lesions. Here we determined whether inflammatory cell-derived progranulin impacts atherosclerosis development.

Methods

Ldlr^-/- mice were transplanted with bone marrow from wild-type (WT) or Grn^-/- (progranulin KO) mice (referred to as Tx-WT and Tx-KO, respectively).

Results

After 10 weeks of high-fat diet feeding, both groups displayed similarly elevated plasma levels of cholesterol and triglycerides. Despite abundant circulating levels of progranulin, the size of atherosclerotic lesions in Tx-KO mice was increased by 47% in aortic roots and by 62% in whole aortas. Aortic root lesions in Tx-KO mice had increased macrophage content and larger necrotic cores, consistent with more advanced lesions. Progranulin staining was markedly reduced in the lesions of Tx-KO mice, indicating little or no uptake of circulating progranulin. Mechanistically, cultured progranulin-deficient macrophages exhibited increased lysosome-mediated exophagy of aggregated low-density lipoproteins resulting in increased cholesterol uptake and foam cell formation.

Conclusions

We conclude that hematopoietic progranulin deficiency promotes diet-induced atherosclerosis in Ldlr^-/- mice, possibly due to increased exophagy-mediated cholesterol uptake. Circulating progranulin was unable to prevent the increased lesion development, consistent with the importance of progranulin acting via cell-autonomous or local effects.