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Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice

AutorArroba, Ana I. ; García-Ramírez, Marta; Cazzoni, Daniele; García Fernández, José Manuel ; Valverde, Ángela M.
Palabras claveDiabetic retinopathy
Microglia
Inflammation
Fecha de publicación2016
EditorElsevier
CitaciónBBA - Molecular Basis of Disease 1862(9): 1663-1674 (2016)
ResumenRetinal diseases linked to inflammation are often accompanied by macrophage/microglial cells activation. However, the dynamics between M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization of microglia during diabetic retinopathy (DR) has not been investigated and it might be therapeutically useful. We assessed microglia polarization in retinas from db/db mice and human diabetic donors and also the microgliamediated anti-inflammatory effects of the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6Ooxomethylidenenojirimycin (R-DS-ONJ). Visual function in mice was evaluated by electroretinogram (ERG). Expression of pro- and anti-inflammatory markers in the retina was analyzed by immunofluorescence, Western-blot and quantitative real-time PCR. Lipopolysaccharide (LPS)-mediated polarization profile was studied in Bv.2 microglial cells in the absence or presence of anti-inflammatory cytokines (IL4/IL13) or R-DSONJ. At 5weeks of age, reduced ERG amplitude values of rod and mixed waves were detected in db/db compared to db/+ mice that correlated with elevated circulating endotoxemia and pro-inflammatory cytokines. At this early stage of DR, the marker of activated microglia Iba-1 co-localized with the M2 marker arginase-1 in the retina. Conversely, in retinas from 8 weeks old db/db mice Iba-1-colocalizedwith active caspase-1, a key component of the inflammasome, reflecting an opposite pattern of microglia polarization. Markers of activated microglia were detected in retinas of diabetic donors. Treatment of Bv.2 cells with LPS and IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards aM2 status at early stages of DR offers novel therapeutic interventions.
URIhttp://hdl.handle.net/10261/150978
DOI10.1016/j.bbadis.2016.05.024
Identificadoresdoi: 10.1016/j.bbadis.2016.05.024
issn: 0925-4439
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