Abstract
ABSTRACTInsulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1−/−), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1−/− mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1−/− mice compared to those in age-matched Igf1+/+ controls. In 6-month-old Igf1−/− retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1−/− mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1+/+ controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1+/+ and Igf1−/− mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1−/− mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1−/− mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing.
Highlights
Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery (Shaw and Grant, 2004; Laviola et al, 2007)
IGF-1 actions are mediated by the IGF-1 receptor (IGF1R), which belongs to the tyrosine kinase membrane receptor family, of which the insulin receptor is the prototype (Werner and LeRoith, 2014)
We have reported that Igf1−/− mice have progressive loss their visual function; these animals being almost blind at 12 months of age
Summary
Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery (Shaw and Grant, 2004; Laviola et al, 2007). IGF-1 is synthesized and secreted by the liver in response to increased concentrations of growth hormone (GH). Concentrations of circulating IGF-1 vary at different developmental stages, increasing during periods of growth such as puberty and decreasing with ageing (Clark et al, 1998; Lacau-Mengido et al, 2000). Anti-inflammatory properties have been attributed to IGF-1 (Hu et al, 2015). All these functions are essential for protecting nerve cells against neurodegenerative processes (Varela-Nieto et al, 2013; Yamamoto et al, 2014). The therapeutic potential of IGF-1 has been demonstrated in animal models of a number of neurodegenerative diseases such as cerebellar ataxia (Fernandez et al, 2005), multiple sclerosis (Chesik et al, 2007) and, as mentioned above, Parkinson disease (Ebert et al, 2008) and Alzheimer disease (Fernandez and TorresAleman, 2012), in which treatment with IGF-1 alleviates neurological symptoms
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