Protective autoimmunity: interferon-gamma enables microglia to remove glutamate without evoking inflammatory mediators.
Glutamate in excessive amounts is a major contributor to neuronal degeneration, and its removal is attributed mainly to astrocytes. Traumatic injury to the central nervous system (CNS) is often accompanied by disappearance of astrocytes from the lesion site and failure of the remaining cells to withstand the ensuing toxicity. Microglia that repopulate the lesion site are the usual suspects for causing redox imbalance and inflammation and thus further exacerbating the neurotoxicity. However, our group recently demonstrated that early post-injury activation of microglia as antigen-presenting cells correlates with an ability to withstand injurious conditions. Moreover, we found that T cells reactive to CNS-specific self-antigens protected neurons against glutamate toxicity. Here, we show that antigen-specific autoimmune T cells, by tailoring the microglial phenotype, can increase the ability of microglia-enriched cultures to remove glutamate. This T-cell-mediated effect could not be achieved by the potent microglia-activating agent lipopolysaccharide (LPS), but was dose-dependently reproduced by the Th1 cytokine interferon (IFN)-gamma and significantly reduced by neutralizing anti-IFN-gamma antibodies. Under the same conditions, IFN-gamma had no effect on cultured astrocytes. Up-regulation of glutamate uptake induced by IFN-gamma activation was not accompanied by the acute inflammatory response seen in LPS-activated cultures. These findings suggest that T cells or their cytokines can cause microglia to adopt a phenotype that facilitates rather than impairs glutamate clearance, possibly contributing to restoration of homeostasis.
Shaked
I
I
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Tchoresh
D
D
Gersner
R
R
Meiri
G
G
Mordechai
S
S
Xiao
X
X
Hart
R P
RP
Schwartz
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015551:Autoimmunity / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects*; D004676:Myelin Basic Protein / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020221:Optic Nerve Injuries / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010586:Phagocytes / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050794:STAT1 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D000097382:CD68 Molecule
D000906:Antibodies; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496318:Nos2 protein, rat