Although IGF-I has been recognized for its peripheral effects in growth and metabolism, it has a role in the CNS as a neurotrophic peptide triggering prosurvival signaling pathways responsible for activation of antiapoptotic cascades, enhancement of nerve growth, and promotion of synaptic plasticity.
49 Moreover, IGF-IR signaling reduces neuroinflammation-dependent sensitivity of neurons to the proparkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
50 In the retina, early intervention with systemic IGF-I in diabetic rats inhibits neuroretinal cell death.
51 However, at the molecular level the impact of the chronic inflammatory environment, which is present in the retina in insulin resistance and T2DM,
52 in the IGF-IR signaling in retinal cells has not been investigated in depth. Taking into account these previous findings, this study has identified for the first time a negative cross-talk between signaling pathways activated by the proinflammatory milieu and the IGF-IR/Akt neuroprotective pathway in photoreceptors that are major contributors to diabetes-induced local inflammation in the retina.
53,54 We found that 661W cells are direct targets of proinflammatory cytokines as manifested by a rapid phosphorylation of JNK and p38 MAPK similar to that of peripheral cells during obesity.
40,55,56 Because a previous report described that activation of JNK in response to light preceded apoptosis in 661W cells,
57 our results suggest that under conditions in which chronic inflammation reaches the retina, activation of stress kinases occur as it does in peripheral insulin-sensitive cells. In this regard, the feedback mechanism mediated by JNK responsible of the early phosphorylation of IRS1 at serine 307 that targets it for proteasomal degradation
35 was found in photoreceptors and retinal explants cultured with proinflammatory cytokines. We have successfully used retinal organotypic cultures to characterize pathologic cell death during retinal degeneration.
58 Herein, we made use of these cultures for elucidating the signaling pathways deregulated in DR. Considering these previous findings, long-term (24 hours) exposure of retinal cells and retinal explants to cytokines decreased IGF-IR tyrosine phosphorylation in response to IGF-I and triggered the degradation of IRS1. Intriguing, increased Akt phosphorylation was found in retinal explants treated with cytokines. This might result of compensatory mechanisms that could alter the expression or activity of specific serine phosphatases attempting to counteract the deleterious effects of cytokines. Nevertheless, under these conditions IGF-I was not able to further increase Akt phosphorylation, reflecting the profound IGF-I resistance induced by the proinflammatory milieu. Altogether, our results suggest a negative cross-talk between signaling pathways triggered by proinflammatory cytokines and IGF-IR–mediated signaling in the retina at the level of IGF-IR and IRS1 that constitute a critical node of modulation of the insulin/IGF-I signaling network.
12 This negative cross-talk was directly reflected by decreased Akt phosphorylation. Because it has been demonstrated that the neuroprotective action of IGF-I in vivo is most likely mediated by the PI 3-kinase/Akt pathway,
59 our data strongly suggest that the proinflammatory milieu in the retina might compromise the fate of retinal cells.