Systemic LPS Causes Chronic Neuroinflammation and Progressive Neurodegeneration

Overview

Journal Glia

Specialty Neurology

Date 2007 Jan 5

PMID 17203472

Citations 999

Authors

Liya Qin

Xuefei Wu

Michelle L Block

Yuxin Liu

George R Breese

Jau-Shyong Hong

Darin J Knapp

Fulton T Crews

Affiliations

Soon will be listed here.

Abstract

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.

Citing Articles

Inhibition of histone deacetylase 6 alleviates neuropathic pain via direct regulating post-translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis.

Chi Z, Lu B, Liu R, Pan C, Meng B, Xing X J Neuroinflammation. 2025; 22(1):74.

PMID: 40069860 PMC: 11895277. DOI: 10.1186/s12974-025-03400-y.

Adolescent binge alcohol exposure accelerates Alzheimer's disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling.

Fisher R, Matheny L, Ankeny S, Qin L, Coleman Jr L, Vetreno R Front Aging Neurosci. 2025; 17:1531628.

PMID: 40046779 PMC: 11880232. DOI: 10.3389/fnagi.2025.1531628.

Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.

Ngo H, Srivastava A, Le H, Ayer S, Crotty G, Schwarzschild M BMC Neurosci. 2025; 26(1):19.

PMID: 40038582 PMC: 11877714. DOI: 10.1186/s12868-025-00939-7.

Licochalcone A prevents cognitive decline in a lipopolysaccharide-induced neuroinflammation mice model.

Carrasco M, Guzman L, Olloquequi J, Cano A, Fortuna A, Vazquez-Carrera M Mol Med. 2025; 31(1):54.

PMID: 39930360 PMC: 11812219. DOI: 10.1186/s10020-025-01106-8.

Associations between inflammation and striatal dopamine D2-receptor availability in aging.

Crine V, Papenberg G, Johansson J, Boraxbekk C, Wahlin A, Lindenberger U J Neuroinflammation. 2025; 22(1):24.

PMID: 39885603 PMC: 11783874. DOI: 10.1186/s12974-025-03355-0.

References

Maurizi C . Postencephalitic Parkinson's disease, amyotrophic lateral sclerosis on Guam and influenza revisited: focusing on neurofibrillary tangles and the trail of tau. Med Hypotheses. 2002; 58(3):198-202. DOI: 10.1054/mehy.2000.1224. View

Gao H, Jiang J, Wilson B, Zhang W, Hong J, Liu B . Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease. J Neurochem. 2002; 81(6):1285-97. DOI: 10.1046/j.1471-4159.2002.00928.x. View

Liu B, Gao H, Wang J, Jeohn G, Cooper C, Hong J . Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci. 2002; 962:318-31. DOI: 10.1111/j.1749-6632.2002.tb04077.x. View

Nadeau S, Rivest S . Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14. J Immunol. 2002; 169(6):3370-81. DOI: 10.4049/jimmunol.169.6.3370. View

Polazzi E, Contestabile A . Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci. 2002; 13(3):221-42. DOI: 10.1515/revneuro.2002.13.3.221. View

Lehnardt S, Massillon L, Follett P, Jensen F, Ratan R, Rosenberg P . Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003; 100(14):8514-9. PMC: 166260. DOI: 10.1073/pnas.1432609100. View

Carvey P, Chang Q, Lipton J, Ling Z . Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease. Front Biosci. 2003; 8:s826-37. DOI: 10.2741/1158. View

McGeer P, Schwab C, Parent A, Doudet D . Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol. 2003; 54(5):599-604. DOI: 10.1002/ana.10728. View

Qin L, Liu Y, Wang T, Wei S, Block M, Wilson B . NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2003; 279(2):1415-21. DOI: 10.1074/jbc.M307657200. View

10.

Nguyen M, DAigle T, Gowing G, Julien J, Rivest S . Exacerbation of motor neuron disease by chronic stimulation of innate immunity in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2004; 24(6):1340-9. PMC: 6730331. DOI: 10.1523/JNEUROSCI.4786-03.2004. View

11.

Ling Z, Chang Q, Lipton J, Tong C, Landers T, Carvey P . Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain. Neuroscience. 2004; 124(3):619-28. DOI: 10.1016/j.neuroscience.2003.12.017. View

12.

Block M, Wu X, Pei Z, Li G, Wang T, Qin L . Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J. 2004; 18(13):1618-20. DOI: 10.1096/fj.04-1945fje. View

13.

Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W . Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science. 1987; 238(4826):522-4. DOI: 10.1126/science.2821621. View

14.

Berkenbosch F, van Oers J, Del Rey A, Tilders F, Besedovsky H . Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science. 1987; 238(4826):524-6. DOI: 10.1126/science.2443979. View

15.

Colton C, Gilbert D . Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 1987; 223(2):284-8. DOI: 10.1016/0014-5793(87)80305-8. View

16.

Sharp B, Matta S, Peterson P, Newton R, Chao C, McAllen K . Tumor necrosis factor-alpha is a potent ACTH secretagogue: comparison to interleukin-1 beta. Endocrinology. 1989; 124(6):3131-3. DOI: 10.1210/endo-124-6-3131. View

17.

Sawada M, Kondo N, Suzumura A, Marunouchi T . Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res. 1989; 491(2):394-7. DOI: 10.1016/0006-8993(89)90078-4. View

18.

Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N . How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med. 2000; 223(1):22-38. DOI: 10.1046/j.1525-1373.2000.22304.x. View

19.

Kim W, Mohney R, Wilson B, Jeohn G, Liu B, Hong J . Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci. 2000; 20(16):6309-16. PMC: 6772569. View

20.

Moss D, Bates T . Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function. Eur J Neurosci. 2001; 13(3):529-38. DOI: 10.1046/j.1460-9568.2001.01418.x. View