Molecular players in neutrophil chemotaxis—focus on PI3K and small GTPases

Abstract

Neutrophil chemotaxis is a process by which individual cells sense a gradient of chemoattractant, polarize, and then migrate toward the chemoattractant. Many features of chemotaxis are shared with other forms of cell migration. We continue to expand our understanding of the mechanisms governing these features. The rapid process through which neutrophils polarize when placed into a gradient of chemoattractant remains least well-understood. Several key molecular players involved in the regulation of polarization have been identified. However, crosstalk among the different molecular players is required to polarize the cell and to maintain cell polarity during directional migration. The mechanism(s) by which this occurs are the subject of current investigations using experimental and computational approaches. Here, we review progress in the field, putting recent observations into context with established findings. We concentrate on the signaling processes regulated by PI3Ks, their lipid products, the role of Rho-family small GTPases, and crosstalk between these important families of regulators.

Analysis of CCR7 mediated T cell transfectant migration using a microfluidic gradient generator

“…Chemoattractant concentration gradient directed immune cell migration (chemotaxis) critically orchestrates the trafficking and homing of various immune cell types in tissues (Cahalan and Parker, 2008;Jin et al, 2008;Gambardella and Vermeren, 2013;Heuzé et al, 2013). T lymphocytes are the key players in adaptive immunity (Garside et al, 1998;Miller et al, 2002;Bromley et al, 2008;John et al, 2009).…”

Characterization of Filifactor alocis and its immune evasion strategies employed against human neutrophils.

“…Ultimately, neutrophils will dissociate from the intermediary chemoattractants and migrate toward the end-target chemoattractants of bacterial origin (119,125). Although the chemoattractants vary significantly in their structure, the receptors for these molecules are all members of the seven-transmembrane helix receptor family which operate through to heterotrimeric G proteins, which further activate downstream pathways responsible for cytoskeletal arrangements and chemotactic functions (119,120,123).…”

“…Since neutrophils are exposed to many chemoattractants that are released at various locations including the vascular endothelium, interstitial cells and the site of infection, it is necessary for them to assimilate and prioritize their response (120,123,124). They can respond to signals from both intermediary chemoattractants (IL-8, platelet activated factor, chemotactic cytokines, leukotriene B 4 (LTB4)) and end target cellular chemoattractants (formyl-methionylleucyl phenylalanine (fMLF), complement fragment C5a, C3a, plasminogen activator), which guide them to a generalized region and then further to a more specific site, where they will encounter their target (118)(119)(120)123).…”

“…They can respond to signals from both intermediary chemoattractants (IL-8, platelet activated factor, chemotactic cytokines, leukotriene B 4 (LTB4)) and end target cellular chemoattractants (formyl-methionylleucyl phenylalanine (fMLF), complement fragment C5a, C3a, plasminogen activator), which guide them to a generalized region and then further to a more specific site, where they will encounter their target (118)(119)(120)123). Ultimately, neutrophils will dissociate from the intermediary chemoattractants and migrate toward the end-target chemoattractants of bacterial origin (119,125).…”

“…Directional movement of leukocytes is necessary for a functional response to a variety of inflammatory signals (117). Leukocytes participate in directional movement toward sites of injury and inflammation by deciphering a chemoattractant gradient, a process referred to as chemotaxis (114,(117)(118)(119)(120).…”