The Complex Role of Innate Immunity in Ocular Angiogenesis

Rajendra S. Apte, MD, PhD
Assistant Professor
Director of Education
Ophthalmology and Visual Sciences
Developmental Biology
Barnes Retina Institute
Washington University School of Medicine
St. Louis, MO

Immune vascular interactions can play an important role in regulating angiogenesis in the eye.^1-3 There is increasing evidence that implicates a critical role for macrophages in this process. Macrophages induce regression of the tunica vasculosa lentis during embryonic development of the lens and play a key role in inhibiting the growth of abnormal blood vessels in age-related macular degeneration (AMD).^1-5 On the contrary, macrophages have also been shown to promote blood vessel growth in murine models of
AMD.^{6, 7} In the tumor micro milieu, the macrophage can either promote or inhibit angiogenesis.⁸

Recent studies have demonstrated that cytokines can influence macrophage-mediated regulation of angiogenesis. In a laser-induced CNV model, mice that lack interleukin-10 (IL-10-/-) are significantly impaired in their ability to generate CNV.^{1, 2} In the eye, IL-10 promotes angiogenesis by altering macrophage function. Polarization of macrophages can play a pivotal role in determining the ultimate effector function of these cells.⁹ Macrophages stimulated in the presence of interferon-gamma  (IFN-γ), lipoploysaccharide (LPS) or granulocyte monocyte colony stimulating factor (GM-CSF) produce high levels of cytokines such as interleukin-12 (IL-12), interleukin-23 (IL-23), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and inducible nitric oxde synthase (iNOS2) with low levels of IL-10, transforming growth factor-beta (TGF-β) and arginase 1(Arg-1). These factors define a classically activated, anti-angiogenic macrophage (M1).  It has been demonstrated that GM-CSF cultured macrophages polarize to an M1 phenotype and can inhibit laser-induced CNV upon injection in to the eyes of host mice.^{1, 2} In the presence of IL-10, interleukin-4 (IL-4), or interleukin-13(IL-13), macrophages become alternatively activated and polarized to a pro-angiogenic phenotype (M2) characterized by high levels of IL-10, TGF-β and Arg-1 and low levels of pro-inflammatory cytokines such IL-6 and TNF-α. This is especially relevant as aging in mice leads to increased IL-10 in the eye and a drift in the macrophage population to a pro-angiogenic phenotype.²

It is important to elucidate those factors that alter macrophage-mediated regulation of angiogenesis. VEGF-A is an important factor in inducing CNV in patients with AMD. Currently, a number of treatments directed at exudative AMD and neovascularization from diabetic retinopathy are focused on neutralization of VEGF-A activity in the eye.¹⁰ Unfortunately, VEGF inhibitors have to be delivered directly into the eye with multiple, frequent intraocular injections, a process that is unpalatable to the patient and one that may rarely be associated with serious ocular adverse events such as infections, hemorrhage and retinal detachments.^10,11 In addition, anti-VEGF therapy, although relatively effective in treating neovascularization, has not been proven efficacious as a) preventive therapy and b) curative in successfully inhibiting CNV without sustained therapy over many months to years. We are now at a point where identifying additional VEGF-independent pathways that stimulate abnormal angiogenesis in the eye is critical in advancing the gains achieved with anti-VEGF therapy and in order to develop preventive therapies. Also, it is crucial to identify safe and effective modalities of targeted delivery of therapeutic agents to the posterior compartment of the eye in order to maximize sustained treatment benefit and minimize local or systemic adverse events.

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