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Neuronal dysfunction leads to Neuroinflammation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Stressed or injured neurons may decrease their synthesis/release of chemokines maintaining microglial cells in a quiescent state (Blank and Prinz, 2013; Chapman et al., 2000; Streit et al., 2001). Consequently microglial cells are becoming reactive, releasing bio-molecules such as cytokines. The pro-inflammatory cytokine IL-6 is known as an inductor of astrocyte reactivity (Chiang et al., 1994).
Neuronal death can lead to the release of intracellular content acting on microglial cells on specific receptors such as DAMPS (Damage Associated Molecular Pathways) (Marin-Teva et al., 2011)
Evidence Collection Strategy
Evidence Supporting this KER
It is well accepted that under normal physiological conditions, microglial cells participate in surveillance of neuronal integrity (Nimmerjahn et al., 2005), and that in case of neuronal stress, injury or death, microglial cells are becoming reactive, what is the initiation of the neuroinflammatory process.
Uncertainties and Inconsistencies
Following paraquat exposure, it was observed that neuronal dysfunction was observed together with astrocyte reactivity, evidenced by increased expression of glial fibrillary acidic protein (GFAP), whereas microglial reactivity was delayed and occurring despite a partial but important neuronal recovery (Sandström et al., 2014). Such observations suggest that the temporal evolution of the inflammatory process is crucial.
It cannot be excluded that toxicant can affect directly glial cells and induce secondarily neuronal injury.
Cell-cell interactions play a key role in the triggering, evolution and consequences of neuroinflammation.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Blank, T. and M. Prinz (2013). "Microglia as modulators of cognition and neuropsychiatric disorders." Glia 61(1): 62-70.
Chapman, G. A., K. Moores, et al. (2000). "Fractalkine Cleavage from Neuronal Membrans Represents an Acute Event in Inflammatory Response to Excitotoxic Brain Damage." J. Neurosc. 20 RC87: 1-5.
Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM (1994) Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. ToxicolApplPharmacol 129: 196-206
Chiang, C.-S., A. Stalder, et al. (1994). "Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice." Dev.Neurosci. 16: 212-221.
Cicchetti F, Lapointe N, Roberge-Tremblay A, Saint-Pierre M, Jimenez L, Ficke BW, Gross RE (2005) Systemic exposure to paraquat and maneb models early Parkinson's disease in young adult rats. Neurobiol Dis 20: 360-371
Davis LE, Kornfeld M, Mooney HS, Fiedler KJ, Haaland KY, Orrison WW, Cernichiari E, Clarkson TW (1994) Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol 35: 680-688
Figiel I, Dzwonek K (2007) TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res 1131: 17-28
Finsen, B. R., M. B. Jorgensen, et al. (1993). "Microglial MHC antigen expression after ischemic and kainic acid lesions of the adult rat hippocampus." Glia 7: 41-49.
Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP (2012) Trimethyltin-induced neurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol 34: 72-82
Liu MC, Liu XQ, Wang W, Shen XF, Che HL, Guo YY, Zhao MG, Chen JY, Luo WJ (2012) Involvement of microglia activation in the lead induced long-term potentiation impairment. PLoS One 7: e43924
Mangano EN, Peters S, Litteljohn D, So R, Bethune C, Bobyn J, Clarke M, Hayley S (2011) Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease. Neurobiol Dis 43: 99-112
Marin-Teva, J. L., M. A. Cuadros, et al. (2011). "Microglia and neuronal cell death." Neuron Glia Biol 7(1): 25-40.
Monnet-Tschudi F, Zurich MG, Pithon E, van Melle G, Honegger P (1995a) Microglial responsiveness as a sensitive marker for trimethyltin (TMT) neurotoxicity. Brain Res 690: 8-14
Monnet-Tschudi F, Zurich MG, Honegger P (1996) Comparison of the developmental effects of two mercury compounds on glial cells and neurons in aggregate cultures of rat telencephalon. Brain Res 741: 52-59
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314-1318
O'Callaghan, J. P. (1988). "Neurotypic and gliotypic proteins as biochemical markers of neurotoxicity." Neurotoxicol.Teratol. 10: 445-452.
Pitter, K. L., I. Tamagno, et al. (2014). "The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions." Glia 62(10): 1595-1607.
Sandstrom von Tobel, J., D. Zoia, et al. (2014). "Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures." Toxicol Lett. 10.1016/j.toxlet.2014.02.001
Selvin-Testa A, Loidl CF, Lopez-Costa JJ, Lopez EM, Pecci-Saavedra J (1994) Chronic lead exposure induces astrogliosis in hippocampus and cerebellum. NeuroToxicology 15: 389-402
Streit, W. J., J. Conde, et al. (2001). "Chemokines and Alzheimer's disease." Neurobiol. Aging 22: 909-913.
Taetzsch T, Block ML (2013) Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol 27: 137-149
von Tobel, J. S., P. Antinori, et al. (2014). "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype." Neurotoxicology 44C: 61-70.
Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F (2002) Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116