MACROPHAGE PHAGOCYTOSIS OF MYELIN IN-VITRO DETERMINED BY FLOW-CYTOMETRY - PHAGOCYTOSIS IS MEDIATED BY CR3 AND INDUCES PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA AND NITRIC-OXIDE

Demyelination of axons in the central nervous system (CNS) during mult iple sclerosis (MS) and its animal model experimental allergic encepha lomyelitis (EAE) is a result of phagocytosis and digestion by macropha ges (M phi) and the local release of inflammatory mediators like tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO). We have inve stigated the process of myelin phagocytosis by M phi in vitro using fl ow cytometric analysis. The binding and uptake of CNS-derived myelin w as dose dependent, was abolished in the presence of EDTA and was enhan ced after opsonization with complement. The phagocytosis of opsonized myelin could be inhibited by antibodies directed against complement re ceptor type 3 (CR3). Furthermore, CR3 also contributes to phagocytosis of non-opsonized myelin, e.g. under serum-free conditions. The phagoc ytosis of CNS-derived myelin induced the production of substantial amo unts of TNF-alpha and NO by the M phi. Our results indicate an importa nt role for CR3 in myelin phagocytosis. The induction of TNF-alpha and NO which accompanies this phagocytosis may further contribute to the overall process of demyelination during MS or EAE.