Abstract
BackgroundActivation of resident microglia accompanies every known form of neurodegeneration, but the involvement of peripheral monocytes that extravasate and rapidly transform into microglia-like macrophages within the central nervous system during degeneration is far less clear.MethodsUsing a combination of in vivo ocular imaging, flow cytometry, and immunohistochemistry, we investigated the response of infiltrating cells in a light-inducible mouse model of photoreceptor degeneration.ResultsWithin 24 h, resident microglia became activated and began migrating to the site of degeneration. Retinal expression of CCL2 increased just prior to a transient period of CCR2+ cell extravasation from the retinal vasculature. Proliferation of microglia and monocytes occurred concurrently; however, there was no indication of proliferation in either population until 72–96 h after neurodegeneration began. Eliminating CCL2-CCR2 signaling blocked monocyte recruitment, but did not alter the extent of retinal degeneration.ConclusionsThese results demonstrate that the immune response to photoreceptor degeneration includes both resident microglia and monocytes, even at very early times. Surprisingly, preventing monocyte infiltration did not block neurodegeneration, suggesting that in this model, degeneration is limited by cell clearance from other phagocytes or by the timing of intrinsic cell death programs. These results show monocyte involvement is not limited to disease states that overwhelm or deplete the resident microglial population and that interventions focused on modulating the peripheral immune system are not universally beneficial for staving off degeneration.
Highlights
Activation of resident microglia accompanies every known form of neurodegeneration, but the involvement of peripheral monocytes that extravasate and rapidly transform into microglia-like macrophages within the central nervous system during degeneration is far less clear
Eliminating CCL2-CCR2 signaling blocked monocyte infiltration but did not alter the extent of degeneration. These results demonstrate that the immune response to neurodegeneration includes resident and infiltrated cells, even at very early times, and that monocyte involvement is not limited to disease states that overwhelm or deplete the resident microglial population and does not always hasten degeneration
In vivo imaging reveals transient period of monocyte extravasation In dark-reared mice lacking Arrestin-1, phototransduction signaling in retinal rods is greatly prolonged and results in light-induced photoreceptor degeneration from within an otherwise fully developed, normal retina ([18, 21]; Fig. 1a)
Summary
Activation of resident microglia accompanies every known form of neurodegeneration, but the involvement of peripheral monocytes that extravasate and rapidly transform into microglia-like macrophages within the central nervous system during degeneration is far less clear. Because infiltrating monocytes differentiate into macrophages that become difficult to distinguish from resident immune cells [9], determining the roles of these populations in the progression of degeneration has been difficult. A drawback to this method is that the radiation that kills myeloid cells can kill microglia as well, leading to the establishment of non-microglia macrophages in the retina that out-populate bona fide microglia and obscure the natural dynamics during neurodegeneration [11, 12]. Because the characteristics of both resident and infiltrating cells can change over time, a deeper understanding of their respective roles requires disambiguating their molecular phenotypes and correlating individual phenotypes with cellular behaviors during the onset and progression of neurodegenerative disease ([15,16,17] for review)
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