TIMP-3 suppression induces choroidal neovascularization by moderating the polarization of macrophages in age-related macular degeneration.

Highlights • TIMP-3 suppression could alter the macrophage polarization to M2 type in bone marrow-derived macrophages. • siR-TIMP-3 regulates macrophage polarization to a more pro-angiogenic subtype in RPE/Choroidal tissues with CNV animal model. • OCTA is effective to observe the CNV lesion in BN rat eye, indicating the absence of TIMP-3 might accelerate the growth of CNV lesions. Abstract Purpose To investigate the role of tissue inhibitor of metalloproteinases–3 (TIMP-3) as a key moderator of macrophage polarization in choroidal neovascularization (CNV) lesions of model mice and in bone marrow-derived macrophage (BMDM). Method We used siR-TIMP-3 to transfect BMDM and gave an intravitreal injection of siR-TIMP-3 to laser-induced CNV mice model, real time-PCR and western blot were applied for detecting the expressions of TIMP-3 and macrophages' biomarker. Besides, CNV lesions in different treatment groups of animal model were examined by the optical coherence tomography angiography (OCTA). Results Our experimental data showed that lack of TIMP-3 stimulated M2 polarization proved by real time-PCR and western blot in BMDMs and CNV mice model. Moreover, intravitreal injection of siR-TIMP-3 accelerated CNV formation using OCTA, which indicated that TIMP-3 suppression is related to pro-angiogenesis of M2 macrophage. Conclusion We showed that the absence of TIMP-3 leads to a more pro-angiogenic microenvironment, playing a key role in CNV formation by positively modulating M2 polarization. The role of TIMP-3 in the regulating inflammation and novel therapeutic target of nAMD needs to be further studied. [ABSTRACT FROM AUTHOR]