PTEN function to ‘prioritize’ chemotactic cues and prevent ‘distraction’ in migrating neutrophils

Bryan Heit, Stephen M Robbins, Charlene M Downey, Zhiwen Guan, Pina Colarusso, B Joan Miller, Frank R Jirik & Paul Kubes

2008. Nature Immunology 9(7), 743 - 752

Speaker: 廖宏明                                   Time: 15:00~16:00, Oct. 22, 2008

Commentator: 謝奇璋 老師                Place: Room 601

Abstract:

    During a host response to bacterial infection, neutrophils recruited into the general vicinity of bacteria by intermediary chemoattractants secreted by host cells such as endothelial cells, mast cells and macrophages. However, neutrophils must disengage from the intermediary chemoattractants and migrate unidirectionally toward the bacteria-derived ‘end-target’ chemoattractants¹. The phosphatidylinositol-3-OH kinase (PI(3)K) and tensin homolog (PTEN) pathway, and the p38 mitogen-activated protein kinase pathway both play important roles in neutrophil chemotaxis². In this study, authors found neutrophil chemotaxis to CXCL2 required PI(3)K, whereas chemotaxis to a synthetic formyl peptide (fMLP) required p38. Migrating in opposing gradients of fMLP and CXCL2, neutrophils tended to move toward fMLP. Treating neutrophils with fMLP or CXCL2 gradient, led to accumulation of PtdIns(3,4,5)P₃ in the pseudopod of the cell and accumulation of PTEN in the uropod of the cell. Using Ela2^crePten^fl mice, author found PTEN^-/- neutrophils had increased pseudopod number and tend to move randomly in opposing gradient of fMLP and CXCL2. However, PTEN^-/- neutrophils treated with PI(3)K inhibitor led it to move toward fMLP but not ‘distracted’ by CXCL2. Ela2^crePten^fl mice injected with bacteria had a greater infected region, and needed more time to clear the bacteria. Furthermore, PTEN^-/- neutrophils could not entry the infection site efficiently. After the administration of K/BxN to induce joint inflammation, Ela2^crePten^fl mice had less severity of clinical joint inflammation and the degree of hindpaw swelling. This study proposed a model in which localization of PTEN has a central function in allowing neutrophils to differentiate between and prioritize intermediary versus end-target chemoattractants.

References:

1.      Murdoch, C. & Finn, A. Chemokine receptors and their role in inflammation and infectious diseases. Blood 95, 3032–3043 (2000).

2.      El Heit, B., Tavener, S., Raharjo, E. & Kubes, P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J. Cell Biol. 159, 91–102 (2002).