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Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians-University, Würzburg, Germany
Apoptotic cell death is an established mechanism to terminate an
inflammatory response in rodent or human brains. Microglia, as the
resident phagocyte, is a strong candidate for the clearance of
apoptotic lymphocytes. Apoptosis was induced in cultured autologous
thymocytes and in myelin basic protein (MBP)-specific, encephalitogenic
T cells from Lewis rats by the addition of 0.1 µg/ml
methylprednisolone. The amount of phagocytosis of apoptotic cells was
assessed using an in vitro phagocytosis assay. Supernatants were
collected to measure microglial cytokine secretion. The state of immune
activation in microglia was investigated by a T cell proliferation
assay and by flow cytometric analysis of microglial surface expression
of immune molecules. Microglia ingested specifically apoptotic cells
(apoptotic thymocytes as well as MBP-specific T cells) in contrast to
nonapoptotic control cells (p < 0.0001).
Subsequent secretion of the proinflammatory cytokines TNF-
and IL-12
was significantly decreased, while the secretion of IL-10 and TGF-
was not affected. Furthermore, ingestion of apoptotic cells led to
increased microglial MHC class II expression without concomitant
increase in MHC class I, costimulatory molecules, and ICAM expression.
The Ag-specific activation of MBP-specific T cells in cocultures with
microglia that had ingested apoptotic cells was significantly less than
that of identical T cells that interacted with nonphagocytosing
microglia. Together with negative results obtained in a trans-well
system, this is in support of a cell contact-mediated effect. Microglia
might play an important role in the clearance of apoptotic cells. The
uptake of apoptotic cells by microglia is tolerogenic and results in a
reduced proinflammatory cytokine production and a reduced activation of
encephalitogenic T cells. This might help to restrict an autoimmune
inflammation and minimize damage in the inflamed
brain.
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