Astrocytic factors deactivate antigen presenting cells that invade the central nervous system.
We hypothesized that CNS tissue has the potential to deactivate invading monocytes/macrophages in order to maintain the immune privilege of the brain, and furthermore, that astrocytes are the cells that initiate monocyte/macrophage deactivation. To test this hypothesis, fluorescent prelabeled rat spleen macrophages with typical amoeboid morphology were transferred into organotypic hippocampal slice cultures (OHSCs), where they gradually developed a ramified morphology similar to the appearance of resting microglial cells. This morphological transformation also occurred if macrophages or monocytes were co-cultured with mixed glial cultures or with astrocytoma cells, and ramification was accompanied by reduced expression of adhesion molecules leukocyte function antigen (LFA)-1, intercellular adhesion molecule (ICAM)-1, and major histocompatibility complex (MHC)-class-II molecules. Moreover, treatment of macrophages with astrocyte culture supernatant effectively down-regulated the LPS-induced expression of adhesion- and MHC-class-II-molecules. Astrocyte supernatant-induced inhibition of adhesion and MHC-class-II-molecule expression was mimicked by transforming growth factor (TGF)-beta1, furthermore, this inhibitory effect was diminished by simultaneous treatment with neutralizing anti-TGF-beta-antibodies. In conclusion, our results suggest that astrocyte-derived, soluble factors that are present in the CNS microenvironment deactivate invading macrophages, thus contributing to the maintenance of CNS immune-privilege following impairment of blood-brain-barrier (BBB) integrity.
University Hospital for Orthopedic Surgery Friedrichsheim, Frankfurt am Main, Federal Republic of Germany. Hailer@em.uni-frankfurt.de
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D000818:Animals; D000831:Animals, Newborn; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology*; D002465:Cell Movement; D002490:Central Nervous System / Q000276:immunology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D017077:Culture Media, Conditioned; D000949:Histocompatibility Antigens Class II; D016169:Lymphocyte Function-Associated Antigen-1; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1