Challenging the Paradigm: Anti-Inflammatory Interleukins and Angiogenesis

Abstract

Angiogenesis is a vital biological process, and neovascularization is essential for the development, wound repair, and perfusion of ischemic tissue. Neovascularization and inflammation are independent biological processes that are linked in response to injury and ischemia. While clear that pro-inflammatory factors drive angiogenesis, the role of anti-inflammatory interleukins in angiogenesis remains less defined. An interleukin with anti-inflammatory yet pro-angiogenic effects would hold great promise as a therapeutic modality to treat many disease states where inflammation needs to be limited, but revascularization and reperfusion still need to be supported. As immune modulators, interleukins can polarize macrophages to a pro-angiogenic and reparative phenotype, which indirectly influences angiogenesis. Interleukins could also potentially directly induce angiogenesis by binding and activating its receptor on endothelial cells. Although a great deal of attention is given to the negative effects of pro-inflammatory interleukins, less is described concerning the potential protective effects of anti-inflammatory interleukins on various disease processes. To focus this review, we will consider IL-4, IL-10, IL-13, IL-19, and IL-33 to be anti-inflammatory interleukins, all of which have recognized immunomodulatory effects. This review will summarize current research concerning anti-inflammatory interleukins as potential drivers of direct and indirect angiogenesis, emphasizing their role in future therapeutics.

Keywords: angiogenesis; cytokine; endothelial cell; hypoxia; inflammation; interleukin; macrophage; polarization.

Figure 1

Direct versus Indirect Angiogenesis. Direct angiogenesis results from an interleukin binding directly to its receptor present on an endothelial cell, leading to the induction of angiogenesis. Indirect angiogenesis results from an interleukin inducing macrophage polarization and subsequent VEGF secretion, leading to the same endpoint of angiogenesis.

Figure 2

Interleukin Initiation of Sprouting Angiogenesis. Interleukins are secreted from various effector cells in health and disease. They can either bind to their receptor directly on endothelial cells (1A) to induce expression of proteolytic and proliferative factors, or they can indirectly bind to their receptor on macrophages (1B) to induce M2 family polarization and VEGF production. VEGF can then bind to its receptor on endothelial cells to induce the expression of proteolytic and proliferative factors. Both direct and indirect angiogenesis can lead to proliferation, migration, and tube formation seen in sprouting angiogenesis (3, 4).