Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, USA
Correspondence to Alan Daugherty, Saha Cardiovascular Research Center, University of Kentucky, BBSRB, Room 243, Lexington, KY 40536-0509, USA. Tel: +1 859 323 3512; e-mail: Alan.Daugherty@uky.edu
Atherosclerosis-based cardiovascular diseases have a devastating impact on public health. Therefore, exploring molecular mechanisms of atherosclerosis is an important focus for development of effective therapeutic strategies . This Bimonthly Update summarizes recent publications that have provided new insights into leukocyte-related mechanisms in the development of atherosclerosis.
Macrophage accumulation is a dominant feature of early atherosclerosis and could be due to changes in recruitment, emigration, proliferation, or death. To gain insights into mechanisms provoking macrophage emigration, van Gils et al.[2▪▪] investigated netrin-1, a protein involved in chemorepulsion and chemoattraction of axons. Netrin-1 was present in macrophages of atherosclerotic lesions. Several in-vitro studies were consistent with this protein being an active participant in the atherosclerotic process including lipid loading of cultured macrophages increasing the abundance of netrin-1. Netrin-1 also inhibited macrophage migration by preventing responses to a number of chemokines. In addition, netrin-1 expression in macrophages was a chemoattractant for smooth muscle cells. Supported by these in-vitro data, the authors performed in-vivo studies demonstrating that netrin-1 deficiency in hematopoietic cells reduced hypercholesterolemia-induced atherosclerosis in LDL receptor −/− mice. A macrophage-tracking technique provided evidence that netrin-1 deficiency in hematopoietic cells led to less retention of macrophages in atherosclerotic lesions. Despite not being directly demonstrated, these data inferred that inhibition of netrin-1 might be able to remove lipid-laden macrophages from established atherosclerotic lesions. The effects of netrin-1 in atherosclerosis have been explored previously. In contrast to the studies of van Gils et al.[2▪▪], others reported that netrin-1 delivered via infection with adeno-associated viruses prevented atherosclerosis by reducing leukocyte accumulation [3▪]. Part of the contradiction may be the result of the unusual approach used by Khan et al.[3▪] to measuring atherosclerosis. However, there may also be a context-based explanation because netrin-1 inhibits migration of circulating leukocytes into tissues, thereby it may exert anti-inflammatory effects [4,5]. Since netrin-1 may have multifunctional roles in regulating leukocyte functions, it requires further work to fully explore the effects of this potentially important molecule in the development and progression of atherosclerosis.
Macrophage polarization has been recognized as a critical mechanism in the development of atherosclerosis. Nur77, a nuclear receptor, controls the differentiation and survival of a subtype of Ly6C monocytes, which may regulate macrophage polarization . As simultaneously demonstrated by two research groups [7▪▪,8▪▪], Nur77 deficiency in bone marrow-derived cells augmented hypercholesterolemia-induced atherosclerosis. Although findings from both groups imply that increased atherosclerosis induced by Nur77 deficiency is associated with enhanced polarization of macrophages toward a M1 phenotype, mechanisms explored in the two studies were different and somewhat conflicting . Hanna et al.[7▪▪] found that increased inflammatory responses were associated with enhanced Toll-like receptor 4 and 9 expression and NF-κB-mediated signaling. In contrast, Hamers et al.[8▪▪] defined a mechanism relating to increased expression of stromal cell-derived factor (SDF)-1α. Additionally, the two studies provided contradicting results on whether Nur77 deficiency in macrophages influenced Dil-oxLDL uptake and macrophage migration. Despite the consistent findings on atherosclerosis, the discrepancies of mechanisms in these two studies indicate potentially complex mechanisms and roles of Nur77 in the development of atherosclerosis. Therefore, it is uncertain whether Nur77 could be a desirable target for treating atherosclerosis .
The current literature adds another exciting layer to understand the molecular mechanisms of atherosclerotic development. While pharmacological modulation of macrophage functions by targeting certain critical molecules may provide promising therapeutic approaches for atherosclerosis, the pros and cons of manipulating these components should be assessed thoroughly in order to translate the current findings into effective therapies in clinical patients.
The authors’ research work is supported by the grants from NIH (HL062846 and HL107319).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451:904–913.
2▪▪. van Gils JM, Derby MC, Fernandes LR, et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 2012; 13:136–143.
3▪. Khan JA, Cao M, Kang BY, et al. Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo. Gene Ther 2011; 18:437–444.
4. Ly NP, Komatsuzaki K, Fraser IP, et al. Netrin-1 inhibits leukocyte migration in vitro and in vivo. Proc Natl Acad Sci U S A 2005; 102:14729–14734.
5. Rosenberger P, Schwab JM, Mirakaj V, et al. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 2009; 10:195–202.
6. Hanna RN, Carlin LM, Hubbeling HG, et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol 2011; 12:778–785.
7▪▪. Hanna RN, Shaked I, Hubbeling HG, et al. NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circ Res 2012; 110:416–427.
8▪▪. Hamers AA, Vos M, Rassam F, et al. Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis. Circ Res 2012; 110:428–438.
9. Lefebvre P, Chinetti G, Staels B. Nur77turing macrophages in atherosclerosis. Circ Res 2012; 110:375–377.
This article provides a large amount of in-vitro and in-vivo data demonstrating that netrin-1 contributes to hypercholesterolemia-induced atherosclerosis via a mechanism associated with impaired macrophage emigration.
In contrast to what has been demonstrated by van Gils et al.[2▪▪], this article shows that netrin-1 prevents atherosclerosis via inhibiting leukocyte accumulation.
This article demonstrated that Nur77 deficiency in bone marrow-derived cells augmented atherosclerosis through a mechanism involving enhanced NF-κB signaling.
This article, comparable to [7▪▪], shows that Nur77 deficiency in bone marrow-derived cells increases atherosclerosis. However, the mechanism was focused on enhanced expression of stromal cell-derived factor-1α.
FURTHER RECOMMENDED READING
▪. McAteer MA, Mankia K, Ruparelia N, et al. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. Arterioscler Thromb Vasc Biol 2012; 32:1427–1435. View Full Text | PubMed | CrossRef
This article introduces a new technique to track macrophages in atherosclerosis in a real-time manner using a high-affinity leukocyte-mimetic MRI. This leukocyte-mimetic MRI technique employed dual-ligand microparticles of iron oxide targeting to P-selectin and vascular cell adhesion molecule-1 on endothelial cells during the development and progression of atherosclerosis.
▪. Döring Y, Drechsler M, Wantha S, et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res 2012; 110:1052–1056. View Full Text | PubMed | CrossRef
This article explored a role of the neutrophil granule protein cathelicidin (CRAMP in mouse) in the development of atherosclerosis. Whole body deficiency of CRAMP in ApoE−/− mice led to a reduction of atherosclerotic lesions and less macrophage accumulation. Neutrophils connected to endothelial cells via CRAMP, and promoted monocyte adhesion to endothelium, thereby contributing to atherosclerosis.
▪. Kanter JE, Kramer F, Barnhart S, et al. Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc Natl Acad Sci U S A 2012; 109:E715–724. PubMed | CrossRef
Monocytes isolated from humans and a mouse model of type 1 diabetes had increased expression of long-chain acyl-CoA synthetase 1 (ACSL1), which was associated with inflammation. Myeloid-specific deficiency of ACSL1 in mice inhibited release of inflammatory mediators from macrophages with M1 phenotype, and attenuated atherosclerosis in diabetic mice, but not in nondiabetic mice.
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