Mechanisms of degranulation in neutrophils

Abstract

Neutrophils are critical inflammatory cells that cause tissue damage in a range of diseases and disorders. Being bone marrow-derived white blood cells, they migrate from the bloodstream to sites of tissue inflammation in response to chemotactic signals and induce inflammation by undergoing receptor-mediated respiratory burst and degranulation. Degranulation from neutrophils has been implicated as a major causative factor in pulmonary disorders, including severe asphyxic episodes of asthma. However, the mechanisms that control neutrophil degranulation are not well understood. Recent observations indicate that granule release from neutrophils depends on activation of intracellular signalling pathways, including beta-arrestins, the Rho guanosine triphosphatase Rac2, soluble NSF attachment protein (SNAP) receptors, the src family of tyrosine kinases, and the tyrosine phosphatase MEG2. Some of these observations suggest that degranulation from neutrophils is selective and depends on nonredundant signalling pathways. This review focuses on new findings from the literature on the mechanisms that control the release of granule-derived mediators from neutrophils.

Figure 1

Rho guanosine triphosphatase and SNAP receptor (SNARE) signalling pathways involved in Ca²⁺-dependent neutrophil degranulation. Receptor binding by a chemoattractant leads to G protein-coupled signal transduction (G protein-coupled receptor [GPCR]) through multiple overlapping intracellular pathways to regulate the selective release of neutrophil granules. Some of these pathways may be non-redundant, for example, through G protein-activated guanine nucleotide exchange factors (GEFs) to activate Rac2, which selectively mobilizes primary granules. ER = endoplasmic reticulum; fMLP = F-Met-Lev-Phe; IL = interleukin; InsP3 = inositol 1, 4, 5-triphosphate; LPTF = lactoperin; MMP = matrix metalloprotease; MPO = myeloperoxidase; VAMP = vesicle-associated membrane protein.

Figure 2

Tyrosine kinases associated with chemokine-induced neutrophil degranulation. Receptor binding leads to direct binding of the G protein-coupled receptor (GPCR) by β-arrestins, which also translocate to primary and secondary granules along with src family kinases Hck and Fgr. IL = interleukin; LTF = ; MAP = mitogen-activated protein; MMP = matrix metalloprotease; MPO = myeloperoxidase.