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

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Leukocytes Polarize in Gradients of
Chemoattractants, then Crawl to the Source
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Chemokines Defined by Structure, Classified and
Named by Patterns of Conserved Cysteines
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The Chemokine Fold
C
G.M.Clore A.M.Gronenborn PDB ID 1IL8
N
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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
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Leukocyte Chemoattractants Act Through a Family
of 7-trans-membrane domain G Protein-coupled
Receptors
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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

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The GPCR Superfamily
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Chemokine Receptors Can Bind Many Chemokines, but
are Class-restricted
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Chemokine Receptor Activation Mechanism
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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.)

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Chemokines Act as Tethered Ligands
CKR
CK
Tethering mechanism Genetic or GAGs
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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
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Area Code for Leukocyte Trafficking
Chemoattractants Selectins Integrins
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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

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Chemokine Receptors Regulate Effector T Cell
Balance
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CHEMOKINES A DOUBLE-EDGED SWORD
Host defense
Angiogenesis
Inflammation
Hematopoiesis
chemokines
L H D
Neoplasia
Autoimmune Disease
Atherogenesis
Infection
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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
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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




















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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

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Angiogenesis is Regulated by the Balance of
Angiogenic and Angiostatic CXC Chemokines

-
IFN-g
ELR
Non-ELR
-
Angiogenesis
Wound Healing Chronic
Inflammation
Cancer
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Classification of Viral Chemokine Mimics

• Structure
• -chemokine
• -7TMD protein
• -unique
• Function
• -anti-chemokine
• -chemoattractant
• -gene expression
• -growth factor
• -membrane fusion factor (cell entry)

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The Extended Chemokine Family
(-)
(/-)
()
(/-)
()
Viral Chemokine Binding Proteins (non-7TM)
(-)
(/-)
?
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HIV and Chemokine Mimicry
HIV-1

HIV-1

Progression
Infection
Host Chemokine


Receptors
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HIV-1 Cytotropism and Pathogenesis
M
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TCL
PBMC
M-tropic T-tropic
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Exploitation of Chemokine Receptors by HIV
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CCR5 CXCR4 and HIV Pathogenesis
HIV
X4
R5
CXCR4
CCR5
CD4
CD4
Target Cell
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Chemokines Cancer Metastasis
Murphy (2001) NEJM 345833-835