Regulation of inflammation in choroidal neovascularization in age related macular degeneration
Age related macular degeneration (AMD) is the most common cause of irreversible central vision impairment in people over 50 in industrialized countries, with major societal and financial impacts. AMD is a multifaceted disease provoked by interactions among environmental risk factors and genetic backgrounds in which inflammation plays an important role. Proinflammatory effects cause a disruption of the physiologically immunosuppressive subretinal environment. The ensuing accumulation of mononuclear phagocytes in the subretinal space is central to the etiology of both atrophic and wet forms of AMD. After smoking, obesity is one of the most important modifiable risk factors. We demonstrate that high-fat diets exacerbate choroidal neovascularisation (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low-grade inflammation, increases recruitment of microglia and macrophages to the site of pathological angiogenesis in the eye and ultimately exacerbates CNV. Modifying microbiota can reduce systemic and local choroidal inflammation and attenuate pathological neovascularization and may thus provide minimally intrusive and cost-effective paradigms to prevent or delay exudative AMD. Another therapeutic option that could reduce CNV through inflammatory modulation is locally trapping ligands of NRP1 with a NRP1-derived trap. Ligands for NRP1 are elevated in the vitreous of patients with AMD at times of active CNV. We found that NRP1-expressing MPs promote CNV by mitigating production of inflammatory factors and promoting alternative activation, giving the MPs a pro-angiogenic character. The less inflammatory and more M2-like MPs that are enriched with age and exacerbate CNV can be rendered less detrimental by hindering NRP1 activation. This thesis explores two angles wherein regulation of inflammation can influence the formation of CNV and lays the groundwork for future development of novel effective primary and secondary preventive treatments for AMD.
Neuropiline-1 Inflammation Age related macular degeneration Choroidal neovascularization Obesity Gut Microbiota Angiogenesis Inflammation Retina Neuropilin-1 Mononuclear phagocytes Macrophage polarization.