Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy
Fátima Cano-Cano, Elena Alcalde‐Estévez, Laura Gómez-Jaramillo, Marta Iturregui, Elena M. Sánchez‐Fernández, José M. Garcı́a Fernández, Carmen Ortiz Mellet, Antonio Campos‐Caro, Cristina López‐Tinoco, Manuel Aguilar‐Diosdado, Ángela M. Valverde, Ana I. Arroba
Abstract
Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of ( S S ,1 R )-1-docecylsulfiny-5 N ,6 O -oxomethylidenenojirimycin (( Ss )-DS-ONJ), a member of the sp 2 -iminosugar glycolipid (sp 2 -IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with ( Ss )-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of ( S S )-DS-ONJ in microglia. ( S S )-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.