Neurotoxic Effects of Lipopolysaccharide on Nigral Dopaminergic Neurons Are Mediated by Microglial Activation, Interleukin-1β, and Expression of Caspase-11 in Mice

Abstract

The endotoxin lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, selectively induces degeneration of substantia nigral (SN) dopaminergic neurons via activation of microglial cells in rats and mice. Caspase-11 plays a crucial role in LPS-induced septic shock in mice. We examined the mechanism of LPS neurotoxicity on SN dopaminergic neurons in C57BL/6 mice and caspase-11 knockout mice. Mice were stereotaxically injected with LPS into the SN on one side and vehicle into the SN of the other side. Immunohistochemistry, Western blotting analysis, enzyme-linked immunosorbent assay, and reverse transcriptase-PCR were performed to evaluate damage of SN dopaminergic neurons and activation of microglial cells. Intranigral injection of LPS at 1 or 3 g/l/site decreased tyrosine hydroxylase-positive neurons and increased microglial cells in the SN compared with the contralateral side injected with vehicle at days 7 and 14 post-injection in C57BL/6 mice. Intranigral injection of LPS at 3 g/l/site induced the expression of caspase-11 mRNA in the ventral midbrain at 6, 8, and 12 h postinjection, and the expression of caspase-11-positive cells in the SN at 8 and 12 h post-injection. Moreover, LPS at 3 g/l/site increased interleukin-1␤ content in the ventral midbrain at 12 and 24 h post-injection. LPS failed to elicit these responses in caspase-11 knockout mice. Our results indicate that the neurotoxic effects of LPS on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1␤, and caspase-11 expression in mice.Parkinson's disease (PD) 1 is histologically characterized by degeneration of dopaminergic neurons in the substantia nigra (SN). High concentrations of microglial cells are present in the SN, and activation of these cells has been observed in the SN of PD patients (1, 2). Recent studies postulated that activation of microglia and neuroinflammatory processes may contribute to the pathogenesis of PD (3, 4). Lipopolysaccharide (LPS), a component of the Gram-negative bacterial cell wall, is a potent inducer of inflammation and activator of microglia (5). Long term stimulation of innate immunity by LPS exacerbates motor neurodegeneration in a mouse model of amyotrophic lateral sclerosis, suggesting that the endotoxin LPS could be involved in neurodegenerative diseases caused by chronic peripheral bacterial infections especially in the presence of genetic or environmental risk factors (6).Dopaminergic neurons are far more sensitive to LPS-induced neurotoxicity than ␥-aminobutyric acidergic or serotonergic neurons, and intranigral injection of LPS induces selective and long lasting dopaminergic neurodegeneration via microglial activation in the SN (5). In PD patients, microglial activation, and selective and irreversible dopaminergic neurodegeneration in the SN are seen (1, 2); therefore intranigral injection of LPS is a suitable model for PD (5). With regard to the signal transduction by LPS, caspase-11 is considered to play a major role because resistance to LPS-induced sept...

Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase

“…LPS-activated microglia kill neurons or oligodendrocyte progenitors directly in cell culture via microglial production of IL-1␤, NO⅐, or Nox2-derived ROS (Ma et al, 2002;Li et al, 2005). These same compounds have also been implicated in the neural tissue damage induced by injection of LPS in rodent brain (Iravani et al, 2002;Cai et al, 2003;Arai et al, 2004;Qin et al, 2004). We now show that Nox1 activity markedly promotes microglial production of NO⅐ and IL-1␤ triggered by LPS.…”

Microglia Cells Protect Neurons by Direct Engulfment of Invading Neutrophil Granulocytes: A New Mechanism of CNS Immune Privilege

“…This was a rather unexpected finding, because numerous studies demonstrated that microglia preacti- vated by inflammatory mediators are strongly neurotoxic (Arai et al, 2004;Minghetti et al, 2004;Qin et al, 2004;Fordyce et al, 2005;Huang et al, 2005). However, a close inspection of these studies shows that microglial activation was achieved by exposure to microbial products (Arai et al, 2004;Qin et al, 2004;Huang et al, 2005) or viral particles (Lim et al, 2003;Minghetti et al, 2004). Lipopolysaccharide (LPS) or viral particles are well known to trigger a massive immune cell reaction via Toll-like receptors (TLRs) (Kawai and Akira, 2006).…”

Interferon β induces mature dendritic cell apoptosis through caspase-11/caspase-3 activation

“…The main substrates of inflammatory caspases, activated through intracellular NOD-like receptors organized in inflammasomes, are cytokines such as pro-IL-1␤, pro-IL-18, and IL-33, and executioner caspases such as caspase-3. Murine caspase-11 is highly induced in hematopoietic cells by LPS and IFN␤ or IFN␥, 10,25,48 leading to apoptosis through activation of caspase-3. 10,14,23,24,49,50 Functional studies of the caspase-11 promoter identified 2 essential sites, an NF-B and a STAT-1 binding site.…”