ELEVATED COMPLEMENT C5A RECEPTOR EXPRESSION ON NEURONS AND GLIA IN ASTROCYTE-TARGETED INTERLEUKIN-3 TRANSGENIC MICE

Evidence from several central nervous system (CNS) inflammatory diseas e models suggests that intrathecal complement synthesis may contribute to early inflammatory events in the brain. In this study, we examined the expression of the receptor for C5a (C5aR), a potent inflammatory and chemotactic factor, in the brains of transgenic mice with constitu tive astrocyte expression of interleukin-3 (IL-3), a hematopoietic and immunomodulatory cytokine. By in situ hybridization, we demonstrated that cells infiltrating the cerebellar meninges, the cerebellum, and d emyelinating lesions in the cerebellum were strongly positive for C5aR mRNA. By immunohistochemistry, the infiltrating cells expressing the C5aR were identified as macrophages based on staining with antibodies to the complement receptor type 3 and F4/80, a mouse macrophage-specif ic marker. In addition, some of the cells in cerebellar lesions were p ositive for the astrocyte-specific marker, glial fibrillary acidic pro tein, suggesting that a subpopulation of astrocytes in these lesions e xpress elevated levels of the C5aR. Increased C5aR expression was also observed in cortical neurons in the occipital cortex and in pyramidal neurons in the cornu ammonis and subiculum of the hippocampus, at bot h the protein and mRNA levels. These data suggest that IL-3 may play a n immunomodulatory role in C5aR expression on several cell types in th e brain and that increased C5aR expression correlates with the patholo gy seen in this model. The transgenic mice used in this study provide a useful tool for characterizing the mechanism of regulation of the C5 aR expression and for examining the functions of this chemotactic rece ptor in CNS inflammation. (C) 1998 Wiley-Liss, Inc.