title: Rab27a regulates GM-CSF-dependent priming of neutrophil exocytosis.
abstract: Neutrophil secretory proteins are mediators of systemic inflammation in infection, trauma, and cancer. In response to specific inflammatory mediators, neutrophil granules are mobilized and cargo proteins released to modulate the microenvironment of inflammatory sites and tumors. In particular, GM-CSF, a cytokine secreted by several immune, nonimmune, and tumor cells, regulates neutrophil priming and exocytosis. Whereas a comprehensive understanding of this process is necessary to design appropriate anti-inflammatory therapies, the molecular effectors regulating GM-CSF-dependent priming of neutrophil exocytosis are currently unknown. With the use of neutrophils deficient in the small GTPase Rab27a or its effector Munc13-4, we show that although both of these secretory factors control matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) exocytosis in response to GM-CSF, their involvement in exocytosis after GM-CSF priming is very different. Whereas GM-CSF priming-induced exocytosis is abolished in the absence of Rab27a for all secondary stimuli tested, including TLR7, TLR9, and formyl peptide receptor 1 (Fpr1) ligands, cells lacking Munc13-4 showed a significant exocytic response to GM-CSF priming. The mobilization of CD11b was independent of both Rab27a and Munc13-4 in GM-CSF-primed cells unless the cells were stimulated with nucleic acid-sensing TLR ligand, thus highlighting a role for both Rab27a and Munc13-4 in endocytic TLR maturation. Finally, the observation that the absence of Rab27a expression impairs the exocytosis of MMP-9 and MPO under both primed and unprimed conditions suggests that Rab27a is a possible target for intervention in inflammatory processes in which GM-CSF-dependent neutrophil priming is involved.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Ramadass
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jennifer Linda
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA scatz@scripps.edu.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Catz
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D051217:Toll-Like Receptor 9; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins
keywords: Munc13-4; TLR7; TLR9; cancer; systemic inflammation