Choroidal neovascularization is inhibited via an intraocular decrease of inflammatory cells in mice lacking complement component C3.
In early age-related macular degeneration (AMD), complement component C3 can be observed in drusen, which is the accumulation of material beneath the retinal pigment epithelium. The complement pathways, via the activation of C3, can upregulate the expression of cytokines and their receptors and the recruitment of inflammatory leukocytes, both of which play an important role in the development of choroidal neovascularization (CNV) in exudative AMD. Laser-induced CNV lesions were found to be significantly smaller in C3(-/-) mice than in wild-type mice. By using flow cytometry, we demonstrated that the proportions of intraocular granulocytes, CD11b(+)F4/80(+)Ly6C(hi) and CD11b(+)F4/80(+)Ly6C(lo) cells, were lower in C3(-/-) mice than in wild-type mice as early as day 1 after laser injury, and the proportions of granulocytes and three macrophage/monocyte subsets were significantly lower on day 3. In contrast, C3(-/-) mice had more granulocytes and CD11b(+)F4/80(+)Ly6C(hi) cells in peripheral blood than wild-type mice after injury. Further, the expression levels of Vegfa164 were upregulated in intraocular Ly6C(hi) macrophages/monocytes of C3(-/-) mice, but not as much as in wild-type mice. Collectively, our data demonstrate that despite a more pronounced induction of systemic inflammation, inhibition of complement factor C3 suppresses CNV by decreasing the recruitment of inflammatory cells to the lesion.
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.
Xue
X
Tan
Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Ubiquitous Health Informatics, School of Medicine, The University of Tokyo, Tokyo, Japan.|Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
Katsuhito
K
Fujiu
Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Ichiro
I
Manabe
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.
Junko
J
Nishida
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.
Reiko
R
Yamagishi
Department of Ubiquitous Health Informatics, School of Medicine, The University of Tokyo, Tokyo, Japan.
Ryozo
R
Nagai
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan.|Jichi Medical University, Tochigi, Japan.|Singapore Eye Research Institute, Singapore, Singapore.|Medical Retina Department, Singapore National Eye Center, Singapore, Singapore.
Yasuo
Y
Yanagi
D000818:Animals; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology*; D003176:Complement C3 / Q000378:metabolism*; D004195:Disease Models, Animal; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology
D003176:Complement C3