Fc gamma receptor activation in human microglia in response to Cryptococcus neoformans immune complex
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Cryptococcus neoformans is an encapsulated fungal pathogen that is remarkable for its ability to cause central nervous system infections especially in AMS patients. We designed studies to explore the roles of microglial Fcgamma receptors (FcgammaR) in the host defense against C. neoformans infection.;We found that microglia produce several chemokines stimulated by C. neoformans and this process involves FcgammaR since (1) C. neoformans-induced chemokine production required specific antibody; (2) immobilized immunoglobulin induced chemokines in the absence of antigen; and (3) C. neoformans-mAb mediated chemokine production was abolished in FcR null microglia.;We next explored microglial FcR activation with respect to the specific FcgammaR types involved. We found that FcgammaRI and III, but not FcgammaRII, are involved in the chemokine response by challenging microglia with C. neoformans complexed with IgG of various isotypes, with or without FcgammaRII and III blocking antibodies. Further, experiments with various FcgammaR-deficient murine microglia also support the result. Thus, FcgammaRI and III mediated the chemokine production in C. neoformans IC-challenged microglia.;While MIP-1alpha production was usually accompanied by C. neoformans phagocytosis, under certain circumstances we found the two could be dissociated. For instance, cytochalasin D, which abrogated phagocytosis, did not inhibit MIP-1alpha production, suggesting that the mechanisms involved in phagocytosis and chemokine production were not the same. Therefore, the microglial FcgammaR signal transduction pathways leading to these two processes were studied in depth. Using specific inhibitors, we observed that Src and Syk are involved early in FcgammaR signaling leading to both processes. By employing adenoviral mediated gene transfer and specific inhibitors of cell signaling pathways, we found that the PI3K and Ras/MEK/ERK pathways are involved in phagocytosis and MIP-1alpha induction, respectively. We found that NF-kappaB played no role in phagocytosis but affected microglial chemokine production.;Together, we studied the microglial Fc receptor activation in response to C. neoformans-mAb challenge and showed that FcgammaR activation is a powerful means of microglial gene induction. We also showed that distinct FcR subtypes and signaling pathways are involved in phagocytosis and chemokine expression. Our studies indicate a mechanism by which passive antibody can influence the course of cryptococcal disease.