Abstract
Neutrophils play a critical role in the host defense against bacterial and fungal infections, but their inappropriate activation also contributes to tissue damage during autoimmune and inflammatory diseases. Neutrophils express a large number of cell surface receptors for the recognition of pathogen invasion and the inflammatory environment. Those include G-protein-coupled chemokine and chemoattractant receptors, Fc-receptors, adhesion receptors such as selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors such as Toll-like receptors and C-type lectins. The various cell surface receptors trigger very diverse signal transduction pathways including activation of heterotrimeric and monomeric G-proteins, receptor-induced and store-operated Ca2 + signals, protein and lipid kinases, adapter proteins and cytoskeletal rearrangement. Here we provide an overview of the receptors involved in neutrophil activation and the intracellular signal transduction processes they trigger. This knowledge is crucial for understanding how neutrophils participate in antimicrobial host defense and inflammatory tissue damage and may also point to possible future targets of the pharmacological therapy of neutrophil-mediated autoimmune or inflammatory diseases.
Highlights
Neutrophils are the most abundant circulating leukocytes in the human blood
Neutrophils express a large number of G-protein-coupled receptors (GPCRs) that participate in host defense and inflammation (Table 1)
The above results indicate that Gβγ subunits released upon GPCR ligation in neutrophils directly triggers two parallel receptor-proximal signal transduction events: activation of the PLCβ2/3 proteins triggers a Ca2+ signal and activation of conventional protein kinase C (PKC) isoforms whereas activation of PI3Kγ leads to PIP3 production and protein kinase B (PKB)/Akt activation (Fig. 1)
Summary
Neutrophils are the most abundant circulating leukocytes in the human blood. They develop in the bone marrow from the myeloid hematopoietic system and share a number of characteristic features with other myeloid cells such as monocytes/macrophages and mast cells [1,2]. Neutrophils show a condensed and multilobed nuclear morphology (likely reflecting the limited transcriptional activity of the cells) and contain a large number of intracellular granules and vesicles with no prominent staining characteristics [3]. There are several classes of receptors expressed on the surface of neutrophils, including G-protein-coupled seven-transmembrane receptors, Fc-receptors, adhesion molecules like selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors including Toll-like receptors and C-type lectins (Table 1) Activation of those receptors leads to complex cellular activation and elimination processes such as phagocytosis, exocytosis of intracellular granules, production of reactive oxygen species, release of neutrophil extracellular traps, as well as additional responses like chemotactic migration or chemokine and cytokine release. Given the very large amount of information available on that subject, only a small portion of the available data will be discussed, focusing on pathways where genetic data from primary mammalian neutrophils are available and where results may have implications in the understanding, diagnosis and therapy of autoimmune and inflammatory diseases
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