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B. Balasubramaniam, D. A. Carter, E. J. Mayer, A. D. Dick; Microglia-Derived IL-6 Suppresses Neurosphere Generation From Adult Human Retinal Progenitor Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):71.
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During severe retinal degeneration or inflammation there is limited tissue regeneration despite the presence of retinal progenitor cells. Microglia (MG) from adult human retina activated by lipopolysaccharide and interferon gamma (LPS-IFNg) secrete both pro- and anti-inflammatory cytokines (including interleukin-6). IL-6 suppresses neurogenesis. The effect of activated retinal MG on human retinal progenitor cells was studied.
Adult human retinal explants cultured in media supplemented with tumour necrosis factor-alpha (TNFa), transforming growth factor-beta (TGFb) or LPS-IFNg were used to generate activated MG cultures. Explants were removed on day 4 and fresh medium was added to migrated, adherent MG cells. MG conditioned medium (CM) from each culture was removed and concentrated on day 7. Later this medium was added to retinal cell suspensions (RCS) generating neurospheres (NS). MG-CM was analyzed by cytokine bead array. NS generation and survival with added MG-CM was observed in the presence and absence of N2 & FGF. NS counts were performed on days 3, 7 and 10 post feeding. Antibody-mediated IL-6 neutralization assessed the role of IL-6.
All day 7 MG-CM contained elevated levels of IL-6, compared to controls. The highest levels of IL-6 were found in the LPS-IFNg MG-CM. In parallel to this the greatest suppression of NS generation and survival compared to standard conditions was observed with the addition of MG-CM from the LPS-IFNg group. The suppression of NS generation by MG-CM was reversed when IL-6 was neutralised.
Activated adult human retinal MG generate IL-6 which suppresses NS formation, when retinal progenitor cells are cultured under optimal conditions (previously established to involve FGF & N2 supplements). The activation status of retinal MG and infiltrating macrophages depend upon the retinal milieu. Under conditions of massive tissue destruction MG may govern retinal progenitor cell behaviour through soluble factors including IL-6.
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