Abstract
Macrophages have been demonstrated to play a proangiogenic role in retinal pathological vascular growth. Pigment epithelium-derived factor (PEDF) works as a powerful endogenous angiogenesis inhibitor, but its role in macrophage recruitment and polarization is largely unknown. To explore the underlying mechanisms, we first evaluated macrophage polarization in the retinas of the oxygen-induced retinopathy (OIR) mouse model. Compared to that in normal controls, M1- and M2-like macrophages were all abundantly increased in the retinas of OIR mice. In addition, both M1 and M2 subtypes significantly promoted neovascularization in vitro and in vivo. In addition, we found that PEDF inhibited retinal neovascularization by dampening macrophage recruitment and polarization. Furthermore, PEDF inhibited macrophage polarization through adipose triglyceride lipase (ATGL) by regulating the activation of MAPKs and the Notch1 pathway, as we found that the phosphorylation of MAPKs, including p38MAPK, JNK and ERK, as well as the accumulation of Notch1 were essential for hypoxia-induced macrophage polarization, while PEDF significantly dampened M1 subtype-related iNOS and M2 subtype-related Arg-1 expression by inhibiting hypoxia-induced activation of Notch1 and MAPKs through ATGL. These findings reveal a protective role of PEDF against retinal neovascularization by regulating macrophage recruitment and polarization.
Highlights
Tufts are greatly reduced by general macrophage depletion by clodronate liposomes in oxygen-induced retinal (OIR) mouse model[9]
Given that macrophages play a proangiogenic role in retinal pathological vascular growth and Pigment epithelium-derived factor (PEDF) works as a powerful endogenous angiogenesis inhibitor whose role in macrophage recruitment and polarization is largely unknown, we investigated whether PEDF could mediate neovascularization by regulating macrophage recruitment and polarization
The flow cytometry results showed that in addition to M1 macrophages, there were many more M2 macrophages that had infiltrated in the retinas of the OIR model than that of the control group, and the M2 macrophages accounted for approximately 15% and 4% of the total macrophages, respectively (Fig. 1a,b)
Summary
Tufts are greatly reduced by general macrophage depletion by clodronate liposomes in OIR mouse model[9]. The M2 phenotype expresses CD206, CD163, CCL22 and arginase-1 (Arg-1) under IL-4, IL-10, TGF-βand IL-13 stimulation[10,11] Both M1- and M2-like phenotypes are found in ROP5; their respective roles in neovascularization are not well studied. Some studies have shown that M2-like macrophages, rather than M1, play a major role in enhancing retinal pathological neovascularization[12]. Whether PEDF could mediate neovascularization of the retina by regulating macrophage recruitment and polarization in the pathogenesis of ROP still needs to be investigated. Given that macrophages play a proangiogenic role in retinal pathological vascular growth and PEDF works as a powerful endogenous angiogenesis inhibitor whose role in macrophage recruitment and polarization is largely unknown, we investigated whether PEDF could mediate neovascularization by regulating macrophage recruitment and polarization. PEDF dampened neovascularization by regulating hypoxia-induced MAPKs and Notch[1] activation through its receptor ATGL
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