Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

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 (SS,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-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 (SS)-DS-ONJ in microglia. (SS)-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.

Unravelling the Inflammatory Processes in the Early Stages of Diabetic Nephropathy and the Potential Effect of (Ss)-DS-ONJ

“…The anti-inflammatory role of ( S S )-DS-ONJ has been detected in other pathological complications associated with T1DM, such as diabetic retinopathy [ 34 ]. The EMT represents an underlying inflammatory process that concurs with the development of fibrosis, as the final step of EMT and renal failure.…”

“…Increasing evidence suggests that sp 2 -IGLs may offer anti-inflammatory protection against diabetic complications [ 33 ]. Our group has recently demonstrated the anti-inflammatory effect of the ( S S )-DS-ONJ compound on neuro-immunomodulation during Diabetic Retinopathy (DR) progression [ 34 ]. Given that inflammation is one of the first mechanisms underlying DN, compounds capable of modulating inflammation could be considered powerful candidates for the treatment of DN.…”

Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative, Leishmanicidal and Anti-Inflammatory Properties

“…The ensemble of data collected on the immunomodulatory behavior of sp 2 -IGLs [45][46][47][48][49][50][51][52][53][54][55] instils that linear aliphatic tails with a length equal or higher than C 8 are required to elicit significant anticancer, antiparasitic and/or anti-inflammatory responses. Accordingly, we focused on n-octyl and n-docecyl aglycone lipid tails in this study.…”

“…It has been already capitalized in the design of specific glycosidase inhibitors and effectors [36,37], lectin ligands [38][39][40][41] and tumor-associated carbohydrate antigen (TACA) mimics [42,43], including a sp 2 -iminosugar glycopeptide-based anticancer vaccine [44]. Conjugates conjoining a sp 2 -minosugar glycone and an α-oriented lipid aglycone, generically termed sp 2 -iminosugar glycolipids (sp 2 -IGLs), have also shown promising abilities as innate immune system regulators with anti-inflammatory [45][46][47], anticancer [48,49] and antiparasitic [50,51] behaviors. A variety of sp 2 -IGLs with C-, N-, Oand S-pseudoglycosidic bonds are already on record [52][53][54].…”

Pathogen‐induced inflammation is attenuated by the iminosugar MON‐DNJ via modulation of the unfolded protein response

“…Bicyclic sphingolipid mimic iminosugars have demonstrated the capacity to reduce inflammation in chronic disease conditions (e.g. diabetic retinopathy) via direct binding of p38a MAPK [ 15 , 16 ]. We therefore sought to investigate the potential for iminosugar to alter the network‐level cellular response to diverse pathogens.…”