Fcγ receptor signaling in primary human microglia: Differential roles of PI-3K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction

Xianyuan Song, Sakae Tanaka, Dianne Cox, Sunhee C. Lee

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Cryptococcus neoformans monoclonal antibody immune complex (IC) induces β-chemokines and phagocytosis in primary human microglia via activation of Fe receptor for immunoglobulin G (FcγR). In this report, we investigated microglial FcγR signal-transduction pathways by using adenoviral-mediated gene transfer and specific inhibitors of cell-signaling pathways. We found that Src inhibitor PP2 and Syk inhibitor piceatannol inhibited phagocytosis, macrophage-inflammatory protein-1α (MIP-1α) release, as well as phosphorylation of extracellular-regulated kinase (ERK) and Akt, consistent with Src/Syk involvement early in FcγR signaling. Constitutively active mitogen-activated protein kinase kinase (MEK) induced MIP-1α, and Ras dominant-negative (DN) inhibited IC-induced ERK phosphorylation and MIP-1α production. These results suggest that the Ras/MEK/ERK pathway is necessary and sufficient in IC-induced MIP-1α expression. Neither Ras DN nor the MEK inhibitor U0126 inhibited phagocytosis. In contrast, phosphatidylinositol-3 kinase (PI-3K) inhibitors Wortmannin and LY294002 inhibited phagocytosis without affecting ERK phosphorylation or MIP-1α production. Conversely, Ras DN or U0126 did not affect Akt phosphorylation. Together, these results demonstrate distinct roles played by the PI-3K and Ras/MEK/ERK pathways in phagocytosis and MIP-1α induction, respectively. Our results demonstrating activation of functionally distinct pathways following microglial FcγR engagement may have implications for human central nervous system diseases.

Original languageEnglish (US)
Pages (from-to)1147-1155
Number of pages9
JournalJournal of Leukocyte Biology
Volume75
Issue number6
DOIs
StatePublished - Jun 1 2004

Keywords

  • Immune complex
  • MEK
  • Macrophage-inflammatory protein-1α
  • Src kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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