bidirectional regulation of neutrophil migration by mitogen-activated protein kinases


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bidirectional regulation of neutrophil migration by mitogen-activated protein kinases

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bidirectional regulation of neutrophil migration by mitogen-activated protein kinases

  1. 1. NATURE IMMUNOLOGY ARTICLES Bidirectional regulation of neutrophil migration by mitogen- Bidirectional regulation of neutrophil migration by mitogen-activated activated protein kinases protein kinases :Prepared By Mohamed Antar Aziz .Molecular Biology lab 2012310880 120521
  2. 2. Bidirectional regulation of neutrophil migration by mitogen- activated protein kinases
  3. 3. IntroductionNeutrophils are granulocytes which are the most abundant type ofwhite blood cells in mammals and form an essential part of the.innate immune systemChemotaxis )the directed migration of cells in response to a gradient ofchemoattractant( is essential for lymphocytes to find antigens and for.neutrophils to find sites of infection and inflammationThe chemotaxis index )CI; the ratio of net migration in the correct.)direction to total migration distance
  4. 4. Chemotactic cells such as blood neutrophils and humanpromyelocytic leukemia )HL60( cells respond to chemoattractantssuch as formyl-Met-Leu-Phe )fMLF( by adopting polarizedmorphology)polarization( and traveling up the gradient )directional.)sensingMitogen-activated protein kinases )MAPKs(, including Erk, Jnk and.p38, are involved in inflammation, apoptosis and migration
  5. 5. RESULTSOpposite roles of Erk and p38 in cell migration*
  6. 6. P38- Ctrl RNAi Erk-RNAiDownregulation of p38 inhibited the directional migration of cells in an fMLFgradient, whereas inhibition of Erk enhanced cell chemotaxis, which suggested thatthese two MAPKs have opposing functions in neutrophil chemotaxis.
  7. 7. Concentration-dependent cell-activity switch for neutrophil chemotaxis and .transmigrationAs high concentrations of chemoattractants are known to inhibit neutrophil orientation
  8. 8. The lower p38 activity and sustained Erk activity were responsible for the impaired . chemotaxis at high concentrations of fMLF These observations indicated that p38 counteracted the stop signal during cell chemotaxis, whereas Erk enhanced it.Activatep38InhibitErk
  9. 9. Higher concentrations of fMLF enhanced receptor internalization and promoted the .cessation of neutrophil migration Receptor internalization acts as a stop signal for directional migration.
  10. 10. .Erk and p38 had opposite effects on FPR1 internalizationHEK 293 Erk activate receptor internalization but p38 inhibits itHL60
  11. 11. GRK2 mediates the stop signal for chemotaxisp38 antagonized recruitment of GRK2 to the membrane while Erk enhanced it.
  12. 12. Binding of p38 to FPR1p38 phosphorylation at Ser342 prevented the interaction of GRK2 with FPR1.Thus, p38 functions as a noncanonical GRK that counteracts the function of GRK2
  13. 13. p38 activation was not altered in cells with RNAi of Erk, and Erk activation was not altered in .cells with RNAi of p38, which indicated p38 and Erk were independently regulated Different Regulation by G protiens of Erk versus p38 70% Inactivate Gi
  14. 14. DISCUSSIONThe two mitogen-activated protein kinases )MAPKs( had opposing roles in.neutrophil traffickingErk potentiated activity of the G protein–coupled receptor kinase GRK2 andinhibited neutrophil migration, whereas the MAPK p38 acted as anoncanonical GRK that phosphorylated the formyl peptide receptor FPR1.and facilitated neutrophil migration by blocking GRK2 functionTherefore, the dynamic balance between Erk and p38 controlled neutrophil’stop‘ and ’go‘ activity, which ensured that neutrophils reached their final .destination as the first line of host defense