Astrocytic factors deactivate antigen presenting cells that invade the central nervous system

Abstract

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)-β1, furthermore, this inhibitory effect was diminished by simultaneous treatment with neutralizing anti-TGF-β- 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.