Therapeutic Targeting of CD47 to Modulate Tissue Responses to Ischemia and Radiation - PubMed (original) (raw)

Therapeutic Targeting of CD47 to Modulate Tissue Responses to Ischemia and Radiation

David R Soto-Pantoja et al. J Genet Syndr Gene Ther. 2011 Oct.

Abstract

CD47 is a widely expressed cell surface receptor that serves as a counter-receptor for signal regulatory protein-α and as a receptor for the secreted matricellular protein thrombospondin-1. Thrombospondin-1 signaling through CD47 regulates cellular signaling pathways that control cell survival, growth, motility, mitochondrial biogenesis, arterial vasoactive responses to physiologic vasodilators and blood flow, and responsiveness to growth factors. Studies employing mice lacking either thrombospondin-1 or CD47 have revealed an important role for this receptor-ligand interaction in tissue responses to injury and stress. These null mice show enhanced recovery from soft tissue fixed ischemic injuries, ischemia reperfusion injuries, and radiation injuries. These studies have led to development of antisense strategies to locally or globally suppress CD47 gene expression. A translation-blocking CD47 morpholino improves tissue survival in skin flap and hindlimb fixed ischemia models, full thickness skin grafts, and a liver ischemia/reperfusion model of organ transplantation in mice. Furthermore, the benefits of morpholino treatment extend to aged mice and mice with dysregulated fat metabolism that characteristically exhibit impaired recovery from ischemic injuries. Activity of the morpholino was also demonstrated for treatment of ischemic injury in miniature pigs. Treatment with the CD47 morpholino protects mice from major effects of ionizing radiation including alopecia, deterioration of muscle function, soft tissue and cutaneous fibrosis, and loss of hematopoietic stem cells in bone marrow. Remarkably, the same treatment does not protect tumors but instead enhances their ablation by irradiation. We discuss prospects for further development of CD47 antisense therapeutics for clinical applications including reconstructive surgery, organ transplantation, angioplasty, and cancer.

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Figures

Figure 1

Figure 1

Regulation of vascular cell signaling by thrombospondin-1 and CD47. A, Angiogenic factors such as VEGF stimulate NO synthesis in endothelial cells by endothelial nitric oxide synthase (eNOS). TSP1 binding to CD47 inhibits activation of the VEGF receptor VEGFR2 and inhibits calcium-dependent activation of the VEGFR2 target eNOS. Within endothelial cells, NO activates soluble guanylate cyclase (sGC) to increase angiogenesis, and this enzyme is another target of inhibitory signaling through CD47. NO can also diffuse into underlying vascular smooth muscle where it activates sGC to cause relaxation and increase blood flow. TSP1 in the vessel wall can antagonize this signal via CD47 on vascular smooth muscle cells. NO diffusing into the vascular lumen limits platelet activation, and TSP1 signaling via CD47 blocks this signal to promote platelet aggregation. B, NO can also act on inflammatory cells to inhibit their activation. TSP1 signaling through this pathway may regulate inflammation, and additional signals through CD47 regulate recruitment and interferon-γ and ROS production.

Figure 2

Figure 2

CD47 signaling controls radiosensitivity. Ionizing radiation induces double strand breaks in DNA, which trigger p53 activation and other damage response pathways that lead to cell death. In the presence of CD47 this involves caspase-dependent apoptosis as well as type III programmed cell death via mitochondria. Down regulation of CD47 by morpholino treatment blocks these death pathways and allows cell survival and continued growth following repair of the radiation damage.

Figure 3

Figure 3

Model for radiosensitization of tumors by CD47 blockade. Radiation of tumors induces expression or surface exposure of damage-associated molecular patterns (DAMP) that can lead to phagocytic clearance by macrophages of killing by cytotoxic cells. High expression of CD47 on tumor cells limits this clearance. Suppression of CD47 by morpholino treatment removes this “don’t eat me” signal and allows destruction of irradiated tumor cells by macrophages or NK cells.

References

    1. Wijnen MH, Vader HL, Roumen RM. Multi-antioxidant supplementation does not prevent an increase in gut permeability after lower torso ischemia and reperfusion in humans. Eur Surg Res. 2002;34:300–305. - PubMed
    1. Meade MO, Granton JT, Matte-Martyn A, McRae K, Weaver B, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med. 2003;167:1483–1489. - PubMed
    1. Kim DS, Ha KC, Kwon DY, Kim MS, Kim HR, et al. Kaempferol protects ischemia/reperfusion-induced cardiac damage through the regulation of endoplasmic reticulum stress. Immunopharmacol Immunotoxicol. 2008;30:257–270. - PubMed
    1. Cheadle C, Watkins T, Ehrlich E, Barnes K, Osama Gaber A, et al. Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts(1,2) Clin Transplant 2010 - PubMed
    1. Kaczorowski DJ, Tsung A, Billiar TR. Innate immune mechanisms in ischemia/reperfusion. Front Biosci (Elite Ed) 2009;1:91–98. - PubMed

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