IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP
Introduction
Insulin-like growth factor-1 (IGF-1) is a multifunctional peptide essential for normal growth and development (Russo et al., 2005) whose pleiotropic actions are mediated primarily by insulin-like growth factor type 1 receptor (IGF-1R), a transmembrane, ligand-activated tyrosine kinase highly homologous to the insulin receptor. Partial inactivation of the IGF-1R increases lifespan and resistance to oxidative stress in the mouse (Holzenberger et al., 2003). Important reciprocal interactions have also been demonstrated between IGF-1 and the pro-inflammatory cytokines that mediate neuro-inflammation (Venters et al., 1999, Ye et al., 2003, Kenchappa et al., 2004). Recent research revealed an anti-inflammatory action, counteracting pro-inflammatory effects of cytokine tumor necrosis factor alpha (TNF-α) (Bluthe et al., 2006). According to the context, IGF-1 would thus appear capable of antagonistic action, pro-oxidative or anti-inflammatory.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), used for modelling the selective dopaminergic cell injury occurring in Parkinson's disease, has dual inflammatory and oxidative actions, but these are non-antagonistic. 1-Methyl-4-phenyl pyridinium (MPP+), the active metabolite of MPTP induces the formation of reactive oxygen species (ROS), such as superoxide or hydroxyl radicals (Blum et al., 2001, Wang et al., 2001, Ryu et al., 2003, Tunez et al., 2004, Watanabe et al., 2005), suggesting that one of the causes of the neurotoxic action is oxidative stress. MPTP concomitantly activates neuro-inflammatory processes, of which the most important are reactive astrogliosis and microgliosis (Reinhard et al., 1988, Francis et al., 1995, Brouillet et al., 1999, Kurkowska-Jastrzebska et al., 1999) and cytokine synthesis (Rousselet et al., 2002, Hebert et al., 2003, Pera et al., 2004, Pattarini et al., 2007). Finally, during MPTP intoxication in mice, IGF-1R levels are upregulated but AKT phosphorylation remained unchanged (D’Astous et al., 2006), showing that while IGF signalling pathways are active in the brain under this neurotoxic insult, IGF signalling activity is not necessarily further induced by this stress.
To better understand the cellular mechanism underlying the antagonistic pro-oxidant and anti-inflammatory action of IGF-1, we submitted heterozygous IGF-1R+/− mice to acute MPTP intoxication. The lesions induced by MPTP were more severe in these mice than in wild-type control animals. The IGF-1R+/− group also showed lower levels of both nitric oxide (NO) and reactive oxygen species (ROS) than controls, both before and after MPTP treatment, but displayed, on the other hand, a dramatically increased neuro-inflammatory response that could well explain the observed increase in neuronal death.
Section snippets
Animals
We established a targeted IGF-1R gene knockout on 129/Sv genetic background (Holzenberger et al., 2003) and backcrossed the mutants for >15 generations to C57BL/6 mice. IGF-1 receptor levels in IGF-1R+/− mice were half those in WT (IGF-1R+/+) mice. Homozygous IGF-1R−/− knockout mutants invariably die minutes after birth. For this study we used 40 IGF-1R+/− and 38 WT (IGF-1R+/+) littermates, as controls. All mice were males and were used at similar age (10–12 weeks) in the different experiments.
IGF-1R+/− mice show increased loss of mesencephalic dopamine neurons after MPTP treatment
Holzenberger et al. (2003) showed that partial inactivation of IGF-1R increases lifespan and resistance to oxidative stress in the mouse, also raising the possibility that this confers relative protection against neurotoxins involving an oxidative stress response such as MPTP (complex I inhibitor). Under control conditions, both IGF-1R+/− animals and their WT littermates showed similar estimated numbers of TH-ir neurons within the SNc (Fig. 1A). After MPTP treatment, WT mice had 26% less
Discussion
Our main objective is to comprehend and further dissect the cellular mechanism behind the dual and antagonistic pro-oxidant and anti-inflammatory roles of IGF-1. Most inflammatory molecules, such as cytokines for instance, are double-edged molecules, either neuroprotective or neurotoxic, depending on the pathophysiological context. However, IGF-1 seems even more particular in the sense that its duality is expressed simultaneously in the same structure. While previous studies using cultured
Conflict of interest
There is no conflict of interest.
Acknowledgements
The University Victor Segalen, the CNRS, the Bordeaux Institute of Neuroscience (INSERM no. 8; CNRS no. 13) provided the infrastructural support for completion of the study.
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Present address: CNRS UMR 5226, INRA UMR1286, Université Bordeaux 2, Bordeaux, France.