Vav1 and PI3K are required for phagocytosis of beta-glucan and subsequent superoxide generation by microglia.
Microglia are the resident innate immune cells that are critical for innate and adaptive immune responses within the CNS. They recognize and are activated by pathogen-associated molecular patterns (PAMPs) present on the surface of pathogens. beta-glucans, the major PAMP present within fungal cell walls, are recognized by Dectin-1, which mediates numerous intracellular events invoked by beta-glucans in various immune cells. Previously, we showed that Dectin-1 mediates phagocytosis of beta-glucan and subsequent superoxide production in microglia. Here, we report that the guanine nucleotide exchange factor Vav1 as well as phosphoinositide-3 kinase (PI3K) are downstream mediators of what is now recognized as the Dectin-1 signaling pathway. Both Vav1 and PI3K are activated upon stimulation of microglia with beta-glucans, and the two proteins are required for phagocytosis of the glucan particles and for subsequent superoxide production. We also show that Vav1 functions upstream of PI3K and is required for activation of PI3K. Together, our results provide an important insight into the mechanistic aspects of microglial activation in response to beta-glucans.
Shah
Vaibhav B
VB
Division of Pharmacology, College of Pharmacy, The Ohio State University, 500W 12th Avenue, Columbus, OH 43210, United States.
Ozment-Skelton
Tammy R
TR
Williams
David L
DL
Keshvara
Lakhu
L
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D047071:beta-Glucans / Q000378:metabolism*
D051567:Proto-Oncogene Proteins c-vav; D017382:Reactive Oxygen Species; C496619:Vav1 protein, mouse; D047071:beta-Glucans; D013481:Superoxides; D019869:Phosphatidylinositol 3-Kinases