Cell migration: PTEN makes neutrophils immune to distraction
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The PI(3)K antagonist PTEN promotes efficient neutrophil migration to sites of infection by prioritizing bacterially derived chemoattractant cues and blocking the response to 'distracting' cues from epithelial and immune cells.
To navigate to sites of infection, neutrophils must prioritize a hierarchy of chemoattractant signals. Neutrophils first sense and migrate towards intermediary endothelial- and immune-derived chemokines, but then detect and home in on short-range cues secreted from the pathogen. Furthermore, neutrophils exposed to both an intermediary cue, such as CXC chemokine ligand 2 (CXCL2) or CXCL8, and an end-target cue, such as formyl peptide (fMLP), will preferentially migrate towards the end-target cue, indicating that it is prioritized when both signals are present. However, it is not yet known how neutrophils 'tune out' the intermediary signals. In Nature Immunology, Paul Kubes and colleagues now report that the phosphatidylinositol-3-OH kinase (PI(3)K) antagonist phosphatase and tensin homolog (PTEN) prioritizes end-stage cues by suppressing PI(3,4,5)P3 accumulation.
Chemotaxis is mediated by discrete PI(3)K and p38 mitogen-activated protein kinase (MAPK) signaling pathways, and previous studies have shown that p38 is essential for end-target signal-mediated migration. Kubes and colleagues found that the presence of fMLP or CXCL8 caused PTEN to localize at the neutrophil trailing membrane, permitting accumulation of PI(3,4,5)P3 — and hence actin polymerization — at the leading edge. Neutrophils placed between fMLP and CXCL8 activated p38 as they migrated towards fMLP. In these cells, PTEN was distributed around the entire cell membrane, which suppressed PI(3,4,5)P3 accumulation. Notably, p38 inhibition reverted this diffuse distribution, leading to accumulation of PI(3,4,5)P3 at the leading edge and migration towards the intermediary cue.
PTEN-deficient mouse neutrophils navigated randomly, rather than directly towards CXCL2. In contrast to wild-type neutrophils, PTEN-deficient neutrophils migrated equally towards CXCL2 and fMLP when placed between opposing cues; PI(3)K inhibition restored the hierarchical migration towards fMLP. To evaluate the possibility that PTEN blocks the 'distracting' CXCL2 signal once neutrophils sense fMLP, neutrophils migrating towards one chemoattractant were exposed to another chemoattractant placed perpendicularly to the direction of migration. Fewer than 5% of wild-type neutrophils turned in response to CXCL2, whereas 25% of PTEN-deficient neutrophils oriented towards CXCL2. Conversely, nearly all wild-type neutrophils migrated towards fMLP when it was used as the second signal, whereas the random migration of PTEN-deficient neutrophils persisted even after addition of fMLP. When examined in vivo, mice with PTEN-deficient neutrophils exhibited a ten-fold higher bacterial burden and prolonged infection due to defective neutrophil recruitment at the site of infection. Thus, PTEN is required to prioritize the end-stage cue, which is essential for an efficient immune response.
These data suggest a model in which neutrophils migrating towards an intermediary cue establish polarized PTEN accumulation away from the leading edge, promoting PI(3)K-mediated migration. End-target chemoattractants activate p38, which causes PTEN to localize around the entire membrane and antagonizes PI(3)K, preventing 'distraction' from intermediary cues. It will be interesting to determine the mechanism by which PTEN is dynamically redistributed, as there is evidence that the p38 signaling pathway may influence PTEN membrane association .
Emily J. Chenette Signaling Gateway
References
Heit, B. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nature Immunology9, 743-752 (2008) | Article | PubMed |
Billadeau, D. D. PTEN gives neutrophils direction. Nature Immunology9, 716-718 (2008) | Article | PubMed |
