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Leukocytes Polarize in Gradients of Chemoattractants, then Crawl to the Source

Leukocytes Polarize in Gradients of Chemoattractants, then Crawl to the Source. Lamellipod. Uropod. Crawling Leukocyte. Resting Leukocyte. CHEMOATTRACTANT (<1%). Structural Signature. Class. Names. CX3C: …………… C XXXC…………………… C …………………C……………… CX3CL1

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Leukocytes Polarize in Gradients of Chemoattractants, then Crawl to the Source

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  1. Leukocytes Polarize in Gradients of Chemoattractants, then Crawl to the Source Lamellipod Uropod Crawling Leukocyte Resting Leukocyte CHEMOATTRACTANT (<1%)

  2. Structural Signature Class Names CX3C: ……………CXXXC…………………… C…………………C……………… CX3CL1 non-ELR CXC: ……………CX__C………………………C…………………C……………… CXCL# ELR CXC: …ELR…CX__C………………………C…………………C……………… CXCL# 4C CC: ……………C___C………………………C…………………C……………… CCL# 6C CC: ……………C___C…………C…………C…………………C……C……… CCL# C: ………………………C……………………………………………C……………… XCL# …but unequally distributed among the 4 classes CXC CC (n~28) (n~16) CX3C (n=1) C (n=2) Chemokines: Defined by Structure, Classified and Named by Patterns of Conserved Cysteines

  3. The Chemokine Fold C G.M.Clore & A.M.Gronenborn PDB ID: 1IL8 N

  4. Chemokine receptors are defined by function, not structure: they bind chemokines and transduce signals. To date all known chemokine receptors are members of the 7TM GPCR superfamily, coupling to Gi. Chemokine Receptors

  5. Leukocyte Chemoattractants Act Through a Family of 7-trans-membrane domain G Protein-coupled Receptors Chemoattractant g a b G protein 7TM Receptor Leukocyte Trafficking

  6. CX C 3 Chemokine Binding Protein Classification Chemokine Subclass Specificity 7TM G Protein-coupled Receptors CXCR1 CXC CXCR2 CXCR3 CXCR4 CXCR5 CXCR6 CCR1 CC CCR2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CCR9 CCR10 XCR1 C CX CR1 3 Chemokine Binding Proteins (7TM architecture) D6 CC Duffy CC & CXC CCX/CKR CC

  7. c y c l i c A M P c h e m o a t t r a c t a n t r e c e p t o r s o f D i c t y o s t e l i u m P o l y p e p t i d e H o r m o n e R H S R e c e p t o r s T R G C H L N e u r o t r a n s m i t t e r R e c e p t o r s R A 1 b R A 2 b H T 2 H T 1 c A 1 P 1 A 2 P 1 a 2 a A R a 2 b A R a 2 c A R H T 1 a M 1 M 5 M 3 M 2 M 4 R h o d o p s i n O p s i n B l O u e L i g h t p s i n G r e e O n p s i R e c e p t o r s n R e d S K R S P R I N e u r o p e p t i d e L 8 I R L A 8 R e c e p t o r s R B F M P I F R R P - P L A 1 L e u k o c y t e 1 C R N a / 5 R T C h e m o a t t r a c t a n t E a P S R A R R e c e p t o r s F R The GPCR Superfamily P r o k a r y o t i c o p s i n s m e t a b o t r o p i c g l u t a m a t e r e c e p t o r s P T H , c a l c i t o n i n , s e c r e t i n r e c e p t o r s ?

  8. Model of MCP-1/CCR2 Interaction Hemmerich et al. Biochemistry, 38:13013, (1999)

  9. Chemokine Receptors Can Bind Many Chemokines, but are Class-restricted

  10. Chemokine Receptor Activation Mechanism

  11. Regulation • Gene expression (cytokines/chemokines, microbes, microbial products, etc.) • GAG association • Post-translational processing (CD26, cathepsin G, TACE) • Endogenous antagonistic chemokines • Decoy receptors (Duffy, D6) • Receptor desensitization (phos/intern.)

  12. Chemokines Act as Tethered Ligands CKR CK Tethering mechanism: Genetic or GAGs

  13. Fractalkine (CX3CL1): an exceptional chemokine • *Expressed on the surface of neurons, • activated vascular endothelium, and in atherosclerotic lesions • *Chemoattracts monocytes, NK cells, CD8+ T *Free and membrane bound forms exist *Membrane-bound form mediates strong integrin-independent adhesion *Both forms act at CX3CR1 Adapted from Rossi, et al. Genomics 1998

  14. WBC aR cR bR a b c d e f Endothelium Area Code for Leukocyte Trafficking Chemoattractants Selectins Integrins

  15. Classification of the Chemokine System by Immunologic Function • Inflammatory • Innate (inducible L -- constitutive R) • CXCR1 & CXCR2  Neutrophils • CCR2, CCR5  Monocytes • CCR3  Eosinophils • Adaptive (inducible L – inducible R) • CXCR3 • CCR2 • CCR5 • CCR3 • CCR9-gut homing • CCR4, CCR10-skin homing • Homeostatic (constitutive L – constitutive R) • CXCR4  Bone marrow • CXCR5  B cell homing to LN • CCR7  mDC & T cell homing to LN

  16. Tonsils Adenoids Classification of Chemokines by Immune Function Cervical Nodes L. Lymph Duct L. Subclavian Vein Thoracic Duct L. Subclavian Vein Thymus Bronchial Nodes Homeostatic CXCL12 Bone Marrow. B CXCL13 LN-B CCL19 LN-T CCL21 LN-T CCL25 gut homing CCL27 skin homing CCL28 mucosal homing Inflammatory CXCL1-8 PMN CXCL9-11 Th1 CCL2-5, 11 MF, Eos, T, NK CX3CL1 MF, Th1, NK Axillary nodes Intercostal Nodes Peyer’s Patches Spleen Peyer’s Patches Appendix Lumbar Nodes Iliac Nodes Inguinal Nodes Bone Marrow

  17. CCR1 CCR3 CCR4 CCR8 CXCR3 CX3CR1 CCR1 CCR2 CCR5 Th2 Th1 Chemokine Receptors Regulate Effector T Cell Balance

  18. CHEMOKINES: A DOUBLE-EDGED SWORD Host defense Angiogenesis Inflammation Hematopoiesis chemokines L H D Neoplasia Autoimmune Disease Atherogenesis Infection

  19. Chemokines/Receptors with Roles in Human Disease CCR5 HIV/AIDS, WNV Duffy P. vivax malaria CXCR4 WHIM syndrome CXCL4 Heparin-induced thrombocytopenia (CXCR4) HIV/AIDS (CX3CR1) Atherosclerosis

  20. Phenotypes Associated with Chemokine or Chemokine Receptor Deficiency Abnormal Development: SDF-1/CXCR4 CXCR2 CCR7/SLC CXCR5/BLC Modulation of Inflammation Eotaxin MIP-1a CCR1, 2, 3, 4, 5, 8 CXCR2, 3 CX3CR1 Altered susceptibility to infection CCR1, 2, 3, 5 CXCR2 Duffy

  21. Duffy and Malaria • 1950s: serologically defined as a minor blood group antigen • 1975: pathologically defined as a virulence factor for P. vivax. Duffy is absent from the red cells of most black Africans who are thereby resistant to vivax malaria. • 1993: molecularly defined as a 7TMD protein, and a promiscuous chemokine binding protein, binding several but not all members of both the CC and CXC groups. The Duffy mutation is in a GATA site in the promoter. • expressed in Purkinje cells of cerebellum, post-capillary venule endothelial cells and CD45RO+ T cells • biochemical and physiological roles undefined

  22. + Angiogenesis is Regulated by the Balance of Angiogenic and Angiostatic CXC Chemokines - + IFN-g ELR Non-ELR - Angiogenesis Wound Healing Chronic Inflammation Cancer

  23. Receptor antagonist Ligand scavenger Classification of Viral Chemokine Mimics • Structure • -chemokine • -7TMD protein • -unique • Function • -anti-chemokine • -chemoattractant • -gene expression • -growth factor • -membrane fusion factor (cell entry)

  24. Host Chemokine Binding Proteins (7TM) Non-chemokine Viral Ligands for Chemokine Receptors Viral Chemokine Receptors (7TM) Host Chemokine Receptors (7TM) Viral Chemokines Non-chemokine Host Ligands for Chemokine Receptors Host Chemokines Human & Viral Orphan Receptors The Extended Chemokine Family (-) (+/-) (+) (+/-) (+) Viral Chemokine Binding Proteins (non-7TM) (-) (+/-) ?

  25. HIV and Chemokine Mimicry HIV-1 HIV-1 Progression Infection Host Chemokine Receptors

  26. CD4 CD4 CD4 AIDS Initial Infection HIV-1 Cytotropism and Pathogenesis M T f M TCL PBMC M-tropic T-tropic

  27. Exploitation of Chemokine Receptors by HIV

  28. CCL3 CCL4 CCL5 CXCL12 5 CCR5D32 4 3 2 1 CCR5 & CXCR4 and HIV Pathogenesis HIV X4 R5 CXCR4 CCR5 CD4 CD4 Target Cell

  29. BreastBloodTarget Organ Chemokines & Cancer Metastasis Murphy (2001) NEJM; 345:833-835

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