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Published on: June 17, 2020
Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration
Christophe Roubeix1,2, Caroline Nous1, Sébastien Augustin1
1Sorbonne Université, INSERM, CNRS, UMR_S 968, Institut de la Vision, 75012, Paris, France.
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.
Insights
Angiotensin II (ATR1) activates splenic monocytes, contributing to age-related macular degeneration (AMD). Blocking ATR1 or removing the spleen reduces AMD progression and vision loss.
Area of Science:
- Ophthalmology
- Immunology
- Neuroscience
Background:
- Age-related macular degeneration (AMD) involves chronic accumulation of activated immune cells in the retina.
- Mononuclear phagocytes, including microglial cells and monocyte-derived cells, drive photoreceptor damage and abnormal blood vessel growth in AMD.
- The role of splenic monocytes, a distinct subset of immune cells, in AMD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the mobilization and function of angiotensin II receptor (ATR1)-expressing splenic monocytes in age-related macular degeneration (AMD) models.
- To determine the therapeutic potential of targeting ATR1+ splenic monocytes for AMD treatment.
Main Methods:
- Utilized acute inflammatory and chronic mouse models of AMD, including ApoE2-expressing mice.
- Employed single-cell RNA sequencing to define the transcriptional signature of splenic monocytes.
- Administered ATR1 antagonists and performed splenectomy to assess therapeutic effects.
Main Results:
- Angiotensin II mobilizes ATR1+ splenic monocytes, which exhibit unique transcriptional profiles and functions compared to bone marrow monocytes.
- Inhibition of ATR1+ splenic monocytes via ATR1 antagonists or splenectomy reduced subretinal immune cell accumulation and choroidal neovascularization in AMD models.
- Both ATR1 antagonist treatment and splenectomy mitigated chronic retinal inflammation and cone degeneration in aged AMD-risk mice.
Conclusions:
- Splenic monocytes are key players in AMD pathogenesis, contributing to retinal inflammation and degeneration.
- Targeting the angiotensin II-ATR1 pathway, specifically in splenic monocytes, represents a promising therapeutic strategy for treating blinding AMD.
- Elevated plasma angiotensin II levels in AMD patients suggest this mechanism is relevant to human disease.
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