Increased lymphocyte activation and atherosclerosis in CD47-deficient mice

Abstract

CD47, also known as integrin-associated protein (IAP), is a transmembrane protein with multiple biological functions including regulation of efferocytosis and leukocyte trafficking. In this study we investigated the effect of CD47-deficiency on atherosclerosis using a model of adeno-associated virus (AAV)-induced hypercholesterolemia. We observed increased plaque formation in CD47 null mice compared to wild-type controls. Loss of CD47 caused activation of dendritic cells, T cells and natural killer (NK) cells, indicating an important role for CD47 in regulating immunity. In particular, Cd47 deficiency increased the proportion of IFN-γ producing CD90 + NK cells. Treatment with depleting anti-NK1.1 monoclonal antibody (mAb), but not depleting anti-CD4/CD8 mAbs, equalized atherosclerotic burden, suggesting NK cells were involved in the enhanced disease in Cd47 deficient mice. Additional studies revealed that levels of CD90 + and IFN-γ + NK cells were expanded in atherosclerotic aorta and that CD90 + NK cells produce more IFN-γ than CD90 - NK cells. Finally, we demonstrate that anti-CD47 (MIAP410) causes splenomegaly and activation of DCs and T cells, without affecting NK cell activation. In summary, we demonstrate that loss of CD47 causes increased lymphocyte activation that results in increased atherosclerosis.

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

“…Myeloid cells showed potential capability to attract other leukocytes, for example CCR5 + T cells through expression of CCL3 (My.1). Moreover, myeloid cells were also predicted to interact with T cells leading to mutual activation, through SIRPA (My)– CD47 (T) 52 ICAM1 (My)– ITGAL (CD8), inducing cytotoxicity and multiple interactions involved in antigen presentation. Lastly, interaction of PDGFB on myeloid subsets with PDGFBR on ECs suggest a possible myeloid-driven induction of angiogenesis, which has been associated with plaque destabilization.…”

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

“…CD47, also referred to as the “Do not-Eat-Me” signal, has received great attention in recent years and has been found to be overexpressed in most cancers [ 77 ]. CD47-blocking antibodies modified the accumulation of central lipid cores by improving the function of phagocytosis in mice with atherosclerosis [ 25 , 78 ]. Therefore, the administration of CD47-blocking antibodies is a feasible anti-inflammatory strategy to mitigate the risks of ACS.…”

Recent Advancements in CD47 Signal Transduction Pathways Involved in Vascular Diseases

“…Several studies have shown that the rate of progression of atherosclerosis of CD47 -/mice was significantly faster than that of wild-type mice [24]. CD47 is widely expressed on various cells as a kind of "don't eat me" signal, causing "cell aggregation," reducing macrophage phagocytosis, increasing the necrotic core, and finally promoting atherosclerosis.…”

“…This result suggests CD47 plays a negative role in the process of atherosclerosis. Meanwhile, CD47 −/− can activate and increase the expression of CD90 + NK cells in CD47-deficient mice, which can produce IFN- γ and further promote atherosclerosis [ 24 ].…”

“…Recent studies have shown that CD47 plays a role in atherosclerosis not through “cell aggregation” but through the dysregulation and activation of NK cells. CD47 deficiency can accelerate the progression of atherosclerosis, because CD47 deficiency and the loss of CD47-SIRP α interaction can cause the activation of T cells and dendritic cells and promote the expression of CD90 on NK cells and the production of IFN- γ , both of which can promote the formation of atherosclerosis [ 24 ].…”