Rab27a regulates GM-CSF-dependent priming of neutrophil exocytosis

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Catz, Sergio D.¹  Johnson, Jennifer Linda¹ 

[1] Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

关键词: Munc13‐;    4;    TLR9;    TLR7;    systemic inflammation;    cancer;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY