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Review
. 2014 Oct:144 Pt A:172-9.
doi: 10.1016/j.jsbmb.2013.10.016. Epub 2013 Oct 31.

25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes

Amy E Riek  1 , Jisu Oh  2 , Isra Darwech  3 , Clare E Moynihan  4 , Robin R Bruchas  4 , Carlos Bernal-Mizrachi  5
Affiliations
Review

25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes

Amy E Riek et al. J Steroid Biochem Mol Biol. 2014 Oct.

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). Vitamin D deficiency is not only more prevalent in diabetics but also doubles the risk of developing CVD. However, it is unknown whether 25-hydroxy vitamin D [25(OH)D3] replacement slows monocyte adhesion and migration, critical mechanisms involved in atherosclerosis progression. In this study, monocytes from vitamin D-deficient diabetic patients were cultured either in the patient's serum or in vitamin D-deficient media with or without 25(OH)D3 treatment. Adding 25(OH)D3 to monocytes cultured in vitamin D-deficient serum or media decreased monocyte adhesion to fibronectin and migration stimulated by monocyte chemotactic protein 1 (MCP-1). Accordingly, 25(OH)D3 decreased adhesion marker β1- and β2-integrin expression and migration receptor chemokine (C-C motif) receptor 2 (CCR2) expression. 25(OH)D3 treatment downregulated monocyte endoplasmic reticulum (ER) stress and scavenger receptor class A, type 1 (SR-A1) expression. The absence of SR-A1 prevented the increased macrophage adhesion and migration induced by vitamin D deficiency. Moreover, the absence of SR-A1 prevented the induction of adhesion and migration and expression of their associated membrane receptors by Thapsigargin, an ER stress inducer. These results identify cellular activation of monocyte/macrophage vitamin D signaling through 25(OH)D3 as a potential mechanism that could modulate adhesion and migration in diabetic subjects. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Keywords: Adhesion; Diabetes; Macrophage; Migration; SR-A1; Vitamin D.

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Figures

Figure 1
Figure 1. 25(OH)D3 suppresses monocyte adhesion in type 2 diabetics
For A–C, monocytes from vitamin D-deficient type 2 diabetics were cultured in vitamin D-deficient or 25(OH)D3-treated patient serum. A. Adhesion assay showing absorbance of cells adhered to fibronectin (n=12, *p<0.05 vs. vitamin D-deficient). B–C. qPCR for mRNA of adhesion receptors B. β1-integrin and C. β2-integrin (n=6, *p<0.001 for both vs. vitamin D-deficient). For D–F, monocytes from vitamin D-deficient type 2 diabetics were cultured in vitamin D-deficient or 25(OH)D3-treated media. D. Adhesion assay showing absorbance of cells adhered to fibronectin (n=12, *p<0.001 vs. vitamin D-deficient). E–F. qPCR for mRNA of adhesion receptors E. β1-integrin and F. β2-integrin (n=6, *p<0.01 for both vs. vitamin D-deficient).
Figure 2
Figure 2. 25(OH)D3 suppresses monocyte migration in type 2 diabetics
Transwell migration assays in monocytes from vitamin D-deficient type 2 diabetics cultured in A. vitamin D-deficient or 25(OH)D3-treated patient serum (n=12, *p<0.001 vs. vitamin D-deficient) and B. vitamin D-deficient or 25(OH)D3-treated media (n=12, *p<0.005 vs. vitamin D-deficient). C–D. qPCR for mRNA of CCR2 from monocytes from vitamin D-deficient type 2 diabetics cultured inC. vitamin D-deficient or 25(OH)D3-treated patient serum and D. vitamin D-deficient or 25(OH)D3-treated media (n=6, *p<0.001 for both vs. vitamin D-deficient).
Figure 3
Figure 3. 25(OH)D3 suppresses monocyte ER stress in type 2 diabetics
Monocytes from vitamin D-deficient type 2 diabetics were cultured in vitamin D-deficient or 25(OH)D3-treated patient serum or media. Western blot for protein expression of scavenger receptor SR-A1 and ER stress proteins p-PERK, p-IRE1α, and CHOP.
Figure 4
Figure 4. SR-A1 knockout suppresses macrophage adhesion and migration induced by vitamin D deficiency
Peritoneal macrophages were isolated from WT and SR-A1−/− mice after normal saline injection and cultured in vitamin D-deficient or 25(OH)D3-treated media. A. Adhesion assay showing absorbance of cells adhered to fibronectin (n=4 per group, p<0.001 by ANOVA, *p<0.05 vs. all other groups by Tukey’s post-test). B. Transwell migration assay (n=4 per group, p<0.005 by ANOVA, *p<0.05 vs. all other groups by Tukey’s post-test). C– E. qPCR for mRNA of adhesion receptors C. β1-integrin and D. β2-integrin and E. migration receptor CCR2 (n=3 per group, p<0.01 by ANOVA for each, *p<0.05 vs. all other groups by Tukey’s post-test).
Figure 5
Figure 5. SR-A1 knockout suppresses macrophage adhesion and migration induced by ER stress
Peritoneal macrophages were isolated from WT and SR-A1−/− mice after normal saline injection and cultured in 25(OH)D3-treated media with or without Thapsigargin. A. Adhesion assay showing absorbance of cells adhered to fibronectin (n=4 per group, p<0.001 by ANOVA, *p<0.05 vs. all other groups by Tukey’s post-test). B. Transwell migration assay (n=4 per group, p<0.001 by ANOVA, *p<0.05 vs. all other groups by Tukey’s post-test, **p<0.05 between indicated groups by Tukey’s post-test). C–E. qPCR for mRNA of adhesion receptors C. β1-integrin and D. β2-integrin and E. migration receptor CCR2 (n=3 per group, p<0.005 by ANOVA for each, *p<0.05 vs. all other groups by Tukey’s post-test).
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References

    1. National diabetes fact sheet: general information and national estimates on diabetes in the United States. Centers for Disease Control and Prevention; 2011. pp. 1–12.
    1. National Diabetes Statistics; N.I.o. Health, editor. NIH publication 08-3892. 2007. pp. 1–24.
    1. Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis. Nat Med. 2002;8(11):1218–1226. - PubMed
    1. Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–241. - PMC - PubMed
    1. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341–355. - PMC - PubMed

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