Chemoattractant receptor signaling and neutrophil acctivation. Involvement of the cytoskeleton

Abstract: Neutrophil granulocytes play a vital role in the host surveillance system and form the first line of defense against microbial infections. The migration of neutrophils to an infected/inflamed tissue is guided by chemoattractants released either from intruding microbes or from activated/damaged host cells. Chemoattractants are recognized by neutrophils through chemoattractant receptors that belong to a large family of pertussis toxin-sensitive, G-protein coupled receptors (GPCRs). Ligand occupation of GPCRs generates signals that activate also the bactericidal systems in neutrophils such as secretion and production of superoxide anion. Being as the principal structure of the neutrophil peripheral cytoplasm, the cytoskeleton serves as the motor for all mechanical responses induced by chemoattractants including adhesion, locomotion, cell spreading and secretion. Inappropriate receptor activation and/or deactivation events may impair host defense and cause tissue damage. Thus, neutrophil GPCR activation is under tight control and regulated by various mechanisms at multiple levels. One such mechanism is the cytoskeleton-directed process that desensitizes the activated receptors and shuts the signaling off. Accumulating experimental evidences in neutrophil research have outlined crucial new implications for the role of actin cytoskeleton in neutrophil GPCR activation. The physical segregation of the activated receptors from the signaling G-proteins and coupling to the cytoskeleton forms one basis for GPCR desensitization. Desensitized GPCRs can be reactivated by subsequent addition of a cytoskeleton-disrupting agent, resulting in superoxide production. Apart from agonist-dependent neutrophil GPCR activation, agonist-independent GPCR activation/reactivation has also been observed. Chemoattractant mediated intracellular Ca2+ transients have long been considered essential for neutrophil activation, however, the reactivation of GPCRs occurs without any intracellular Ca2+ transient. Despite the large structural similarities and similar cellular responses they induced, some fundamental differences exist between different GPCRs with respect to receptor desensitization/reactivation and intracellular signaling. Even the two very closely related formyl peptide receptors, FPR and FPRL1, use distinct signaling pathways to activate neutrophils. The pro-inflammatory effect mediated through FPR may possibly be used as a new approach to antimicrobial chemotherapy, as suggested by the fact that certain antibiotics (bacterial peptide deformylase inhibitors) promote the bacterial release of FPR-activating peptides.