Anti-VCAM1 Monoclonal antibody, clone 530 [eFluor® 450]

Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80(+)VCAM1(+) bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate hemedependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis.

Background. End-stage renal disease (ESRD) is strongly associated with arterial calcification of the tunica media, decreased vascular compliance and sudden cardiac death. Here, we analysed the distribution pattern of uraemic media calcification and concomitant inflammation in mice and men. Methods. Uraemia was induced in DBA/2 mice with high-phosphate diet. Subsequently, we analysed arterial medial calcification using histology, mass spectrometry, and wire myography. Gene expression was quantified using a whole transcriptome array and quantitative PCR. In a cohort of 36 consecutive patients with CKD stage 4-5, we measured the calcium score of the coronary arteries, the ascending thoracic aorta and the infrarenal abdominal aorta using computed tomography scans. Results. Uraemic DBA/2 mice showed only minor calcifications in thoracic aortas, whereas there was overt media calcification in abdominal aortas. The transcriptional profile and immunohistochemistry revealed induction of Vcam1 expression by vascular smooth muscle cells in uraemic abdominal aortas. Macrophages infiltrated the tunica media of the abdominal aorta. Anti-inflammatory treatment did not improve uraemic media calcification in our animal model. Arterial calcifications in ESRD patients showed a similar distribution pattern in computed tomography scans, with higher calcium scores of the abdominal aorta when compared with the thoracic aorta. Conclusion. Taken together, there was a similar heterogeneous pattern of calcification in both mice and humans, where the abdominal aorta was more prone to media calcification when compared with the thoracic aorta. In uraemia, smooth muscle cells of the abdominal aorta showed a phenotypic switch to an inflammatory and osteoblastic phenotype.