Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Abstract

Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson's disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9+ glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism. © 2014 Springer-Verlag Berlin Heidelberg

Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System

“…It has been reported previously that MMP-9 is released from damaged DA neurons (Lorenzl et al, 2004) and induces glial activation (Annese et al, 2015). Similar to these reports, we observed that MPP ϩ treatment induced an increase in MMP-9 activity, as measured by gelatin zymography, in SH-SY5Y neuronal cultures (Fig.…”

“…At the same time, reactive astrocytes also display beneficial characteristics in these models of PD (Voutilainen et al, 2009;Rappold and Tieu, 2010;Yokoyama et al, 2011). In addition, LCN2 produced by activated astrocytes in response to neurodegeneration contributes to neurotoxicity in vitro, suggesting that reactive astrocytes might have neurotoxic properties such as secretion of neurotoxic molecules Bi et al, 2013). Reactive astrocytes also contribute to neuronal impairment through induction of neurotoxic factors in ␤-amyloidtreated astrocytic/neuronal cocultures (Malchiodi-Albedi et al, 2001).…”

“…Together, these results indicate that, even though the crosstalk between damaged neurons and reactive astrocytes remains poorly understood, reactive astrocytes may play detrimental roles in PD under specific pathological conditions. Such conditions include gliosis induced by neuronal injury or toxic insults (Rappold and Tieu, 2010) and the simultaneous loss of neuroprotective functions and gain of neurotoxic properties (Bi et al, 2013). Moreover, reactive astrocytes can produce soluble factors that stimulate microglial activation, resulting in neurodegeneration (Rohl and Sievers, 2005;Ovanesov et al, 2008).…”

“…Nevertheless, the role of LCN2 in EAE remains controversial. Moreover, our group and others reported that reactive astrocytes could secrete LCN2, resulting in neurotoxic effects in vitro Bi et al, 2013). Choy et al (2015) showed that LCN2 expression was increased in the SN after medial forebrain bundle (MFB) transection in vivo, suggesting that an increase in LCN2 levels might be related to PD pathogenesis (Choy et al, 2015).…”

“…LCN2 plays a role in transferring iron into cells (Devireddy et al, 2005). Moreover, intracellular iron accumulation is involved directly in PD pathogenesis Hare et al, 2013;Ward et al, 2014;Ayton et al, 2015;Hare et al, 2015). Therefore, to investigate whether LCN2 upregulation contributes to neurodegeneration through intracellular iron accumulation in DA neurons, we evaluated the neurotoxic effects of recombinant LCN2 protein in the presence of an iron supplement or an iron chelator in the nigrostriatal DA system of mouse brains.…”