1. Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration.
- Author
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Roubeix, Christophe, Nous, Caroline, Augustin, Sébastien, Ronning, Kaitryn, Mathis, Thibaud, Blond, Frédéric, Lagouge-Roussey, Pauline, Crespo-Garcia, Sergio, Sullivan, Patrick, Gautier, Emmanuel, Reichhart, Nadine, Sahel, José-Alain, Burns, Marie, Paques, Michel, Sørensen, Torben, Strauss, Olaf, Guillonneau, Xavier, Delarasse, Cécile, and Sennlaub, Florian
- Subjects
Age-related macular degeneration ,Angiotensin ,Neuroinflammation ,Splenic monocytes ,Humans ,Mice ,Animals ,Aged ,Monocytes ,Angiotensin II ,Macular Degeneration ,Inflammation ,Choroidal Neovascularization - Abstract
Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.
- Published
- 2024