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Infection and Immunity, September 2002, p. 5177-5184, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5177-5184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Fc{gamma} Receptor I- and III-Mediated Macrophage Inflammatory Protein 1{alpha} Induction in Primary Human and Murine Microglia

Xianyuan Song,1 Scott Shapiro,2 David L. Goldman,3 Arturo Casadevall,4 Matthew Scharff,2 and Sunhee C. Lee1*

Departments of Pathology,1 Cell Biology,2 Pediatrics,3 Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 104614

Received 8 March 2002/ Returned for modification 19 April 2002/ Accepted 4 June 2002

Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific Fc{gamma}R types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1{alpha} (MIP-1{alpha}) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of {gamma}1, {gamma}2a, and {gamma}3, but not {gamma}2b isotype, was effective in inducing MIP-1{alpha} in human microglia. Since murine {gamma}2b binds to human Fc{gamma}RII (but not Fc{gamma}RI or Fc{gamma}RIII), these results indicate that Fc{gamma}RI and/or Fc{gamma}RIII is involved in MIP-1{alpha} production. Consistent with this, an antibody that blocks Fc{gamma}RII (IV.3) failed to inhibit MIP-1{alpha} production, while an antibody that blocks Fc{gamma}RIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab')2, induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1{alpha} release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-{kappa}B{alpha}, and MIP-1{alpha} release was suppressed by the antioxidant NF-{kappa}B inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While Fc{gamma}RII-deficient microglia showed little difference from the wild-type microglia, both Fc{gamma}RI {alpha}-chain- and Fc{gamma}RIII {alpha}-chain-deficient microglia produced less MIP-1{alpha}, and the common Fc {gamma}-chain-deficient microglia showed no MIP-1{alpha} release. Taken together, our results demonstrate a definitive role for Fc{gamma}RI and Fc{gamma}RIII in microglial chemokine induction and implicate ERK and NF-{kappa}B as the signaling components leading to MIP-1{alpha} expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.

* Corresponding author. Mailing address: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2666. Fax: (718) 430-8867. E-mail: slee{at}aecom.yu.edu.

Editor: S. H. E. Kaufmann

Infection and Immunity, September 2002, p. 5177-5184, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5177-5184.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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