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      Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration

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          Abstract

          A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.

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          Most cited references145

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          Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

          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. (c) 2007 Wiley-Liss, Inc.
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            p38 MAP-kinases pathway regulation, function and role in human diseases.

            Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.
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              High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                09 May 2019
                May 2019
                : 20
                : 9
                : 2293
                Affiliations
                [1 ]Department of Pharmacology, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Belo Horizonte 31270-901, Brazil; cacaribeiro@ 123456gmail.com (C.R.A.B.); gvnngomes@ 123456gmail.com (G.F.G.)
                [2 ]Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; ecandelario@ 123456ufl.edu
                [3 ]Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany
                Author notes
                [* ]Correspondence: bernd.fiebich@ 123456uniklinik-freiburg.de (B.L.F.); antoniooliveira@ 123456icb.ufmg.br or acpoliveira@ 123456gmail.com (A.C.P.d.O.); Tel.: +49-761-270-68980 (B.L.F.); +55-31-3409-2727 (A.C.P.d.O.); Fax: +49-761-270-69170 (B.L.F.); +55-31-3409-2695 (A.C.P.d.O.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-5826-4330
                https://orcid.org/0000-0003-3631-1989
                Article
                ijms-20-02293
                10.3390/ijms20092293
                6539529
                31075861
                22c66d61-61cc-4e11-a313-892a2557bce8
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 April 2019
                : 05 May 2019
                Categories
                Review

                Molecular biology
                lipopolysaccharide,inflammation,neurodegeneration,alzheimer’s disease,parkinson’s disease,amyotrophic lateral sclerosis,huntington’s disease

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