Neutrophil primary granule release and maximal superoxide generation depend on Rac2 in a common signalling pathway

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Abstract
Neutrophils play an integral role in innate immunity by undergoing degranulation and respiratory burst in response to inflammatory stimuli. Rac2, a monomeric GTP-binding protein, has been shown to be involved in several neutrophil functions, including primary granule release and superoxide (O(2)(-.) generation. We hypothesized that Rac2 is a common signalling molecule required for primary granule translocation and maximal O(2)(-.) production. Using bone marrow neutrophils from Rac2 knockout (KO) mice and wild type C57Bl/6 mice, we found that primary granule elastase and myeloperoxi dase release were absent in Rac2 KO neutrophils upon chemoattractant stimulation. Rac2 KO neutrophils also failed to produce maximal levels of extracellular O(2(-.) generation in response to phorbol myristate acetate (PMA). Although PMA was ineffective at eliciting primary granule mediator release, it induced secondary granule exocytosis in both WT and Rac2 KO neutrophils. Thus, the signalling pathway leading to primary granule release utilized Rac2, which was also necessary for full activation of O(2)(-.) generation in stimulated neutrophils. These findings indicate that O(2)(-.) release and secondary granule secretion may use protein kinase C (PKC) - dependent pathways, whereas primary granule exocytosis appears to rely on PKC-independent signalling events. These findings shed light on possible signalling mechanisms involved in granule secretion from activated neutrophils responding to different stimuli.