title: Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis.
abstract: Photoreceptor apoptosis is a major cause of visual loss in retinal detachment (RD) and several other visual disorders, but the underlying mechanisms remain elusive. Recently, increased expression of monocyte chemoattractant protein 1 (MCP-1) was reported in vitreous humor samples of patients with RD and diabetic retinopathy as well as in the brain tissues of patients with neurodegenerative diseases, including Alzheimer's disease and multiple sclerosis. Here we report that MCP-1 plays a critical role in mediating photoreceptor apoptosis in an experimental model of RD. RD led to increased MCP-1 expression in the Müller glia and increased CD11b+ macrophage/microglia in the detached retina. An MCP-1 blocking antibody greatly reduced macrophage/microglia infiltration and RD-induced photoreceptor apoptosis. Confirming these results, MCP-1 gene-deficient mice showed significantly reduced macrophage/microglia infiltration after RD and very little photoreceptor apoptosis. In primary retinal mixed cultures, MCP-1 was cytotoxic for recoverin+ photoreceptors, and this toxicity was eliminated through immunodepleting macrophage/microglia from the culture. In vivo, deletion of the gene encoding CD11b/CD18 nearly eliminated macrophage/microglia infiltration to the retina after RD and the loss of photoreceptors. Thus, MCP-1 expression and subsequent macrophage/microglia infiltration and activation are critical for RD-induced photoreceptor apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in RD and other CNS diseases that share a common etiology.
authors.affiliation: Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, and Children's Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.forename: Chifuyu
authors.initials: C
authors.lastname: Nakazawa
authors.forename: Kosuke
authors.initials: K
authors.lastname: Noda
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.forename: Haicheng
authors.initials: H
authors.lastname: She
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsubara
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Miyahara
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yin
authors.forename: Larry
authors.initials: L
authors.lastname: Benowitz
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
mesh_terms: D017209:Apoptosis; D002465:Cell Movement; D018932:Chemokine CCL2; D018920:Coculture Techniques; D006801:Humans; D016177:Macrophage-1 Antigen / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D017628:Microglia / Q000502:physiology; D010786:Photoreceptor Cells / Q000473:pathology*; D012163:Retinal Detachment / Q000209:etiology* / Q000473:pathology*
chemical_list: D018932:Chemokine CCL2; D016177:Macrophage-1 Antigen