Progranulin in the hematopoietic compartment protects mice from atherosclerosis

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 TxKO 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.