Progesterone Attenuates Microglial-Driven Retinal Degeneration and Stimulates Protective Fractalkine-CX3CR1 Signaling.
Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue 'Norgestrel' is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel's neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.
Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
Sarah L
SL
Roche
Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
Alice C
AC
Wyse-Jackson
Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, Alicante, Spain.
Violeta
V
Gómez-Vicente
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
Pedro
P
Lax
Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
Ana M
AM
Ruiz-Lopez
Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
Ashleigh M
AM
Byrne
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
Nicolás
N
Cuenca
Cell Development and Disease Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
Thomas G
TG
Cotter
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009644:Norgestrel / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D000073883:CX3C Chemokine Receptor 1; D000697:Central Nervous System Stimulants; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D018696:Neuroprotective Agents; D019707:Receptors, Chemokine; D009644:Norgestrel; D011374:Progesterone