Interleukin‐17A neutralization alleviated ocular neovascularization by promoting M2 and mitigating M1 macrophage polarization

Abstract

SummaryNeovascularization (NV), as a cardinal complication of several ocular diseases, has been intensively studied, and research has shown its close association with inflammation and immune cells. In the present study, the role of interleukin-17A (IL-17A) in angiogenesis in the process of ocular NV both in vivo and in vitro was investigated. Also, a paracrine role of IL-17A was demonstrated in the crosstalk between endothelial cells and macrophages in angiogenesis. In the retinas of mice with retinopathy of prematurity, the IL-17A expression increased significantly at postnatal day 15 (P15) and P18 during retinal NV. Mice given IL-17A neutralizing antibody (NAb) developed significantly reduced choroidal NV and retinal NV. Studies on vascular endothelial growth factor (VEGF) over-expressing mice suggested that IL-17A modulated NV through the VEGF pathway. Furthermore, IL-17A deficiency shifted macrophage polarization toward an M2 phenotype during retinal NV with significantly reduced M1 cytokine expression compared with wild-type controls. In vitro assays revealed that IL-17A treated macrophage supernatant gave rise to elevated human umbilical vascular endothelial cell proliferation, tube formation and VEGF receptor 1 and receptor 2 expression. Therefore, IL-17A could potentially serve as a novel target for treating ocular NV diseases. The limitation of this study involved the potential mechanisms, such as which transcription accounted for macrophage polarization and how the subsequent cytokines were modulated when macrophages were polarized. Further studies need to be undertaken to definitively determine the extent to which IL-17A neutralizing anti-angiogenic activity depends on macrophage modulation compared with anti-VEGF treatment.

Macrophage Plasticity and Function in the Eye and Heart

“…Elimination of macrophage recruitment via Ccr2 knockout diminished the development of AMD disease phenotypes after CEP-MSA injection, demonstrating a role of M1-like inflammatory macrophages in the development of early AMD disease phenotypes (RPE dysfunction and loss) [85]. Others have demonstrated a possible role of M1-like macrophages in mediating the later phenotype of neovascularization [86]. Specifically, in both laser-induced CNV and an oxygen-induced model of retinopathy of prematurity, removal of Il17a by genetic knockout or neutralizing antibody reduced the M1 population and increased the M2 population, and caused reduced neovascularization in both disease models relative to controls.…”

Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

“…Conditions of RPE degeneration, including age-related macular degeneration (AMD) and retinitis pigmentosa, are believed to involve dysregulated immune responses (12,13). Although extensive studies have been performed to demonstrate how activated immune cells and complement proteins contribute to the inflammatory and angiogenic responses in the outer retina (14)(15)(16)(17), it has not been established whether the innate immune cells of the choroid can exert protective effects against RPE injury.…”

Altered Long Non-coding RNAs Involved in Immunological Regulation and Associated with Choroidal Neovascularization in Mice

“…A number of studies have reported that different cytokines, such as IL-10, IL-12, IFN-γ, IL-17, IL-18 and IL-33, may play a role in the pathogenesis of CNV [33][34][35][36][37]. The pro-and anti-angiogenic effects of the cytokines relevant to Th1, Th2 and Th17 cells, participate in a complicated immunological network [38].…”