Chemokines and Chemokine Receptors Flashcards
What are chemokines?
“Chemotactic cytokines”
First discovered in 1980’s
Polypeptides of similar structures
Orchestrate migration and trafficking of cells to tissue
* Homeostasis
* Inflammation
Structural Characteristics of Chemokines
Small molecules (60-100 amino acids) with a low molecular weight (8-14kd)
Tha largest family of cytokines
* Over 50 have been identified
* Strcuturally related
Sub-classifed based on structure
* Highly conserved cysteine (Cys) motifs in their aa sequence
* Most have four characteristic Cys
Classification of chemokine subclass
Based on the number and spacing of the conservred Cys residues in their amino termini
CXC-alpha
CC-beta
C-gamma
CX3C-delta
Structural Characteristics of Chemokines
Two disulfide bonds link the 1st and 3rd cysteine and the 2nd and 4th
Membrane bound CXC3 has a mucin-like domain and an intercytoplasmic domain
* Fractalkine (in humans)
* Neurotactin (in mice)
Chemokine Function
- Homeostatic
- Inflammatory
Chemokine Function
Homeostatic
Constitutive
Development of B and T cells in secondary lymphoid organs
Immune surveillance
* Skin and mucosal surfaces express increased levels of chemokines
Chemokine Function
Inflammatory
Induced
* IL-1
* TNF-alpha
* IFN-gamma
* Microbial products (LPS)
* Trauna/tissue damage
Chemokine Receptors
- Membrane bound molecules
- Composed of 7 transmembranes domains couples to G proteins at C terminal
- Receptors are internalized following chemokine binding and subsequently recycled
- Highly promiscuous - one receptor has multiple ligands
- Restrcited to same subclass of ligand
- Some restricted to certain cell types
- Some widely expressed
Chemokines Receptors Function
Constitutively expressed
Constitutive receptors can be down-regulated
* CCR2 down regulated by LPS, making cells unresponsive to MCP-1
Inducible
IL-2 sitmulation of lymphocytes induces CCR1 and CCR2
Induced expression restricted to a cell’s state of activation/differentation
* CXCR3 - Th1 cells
* CCR3 - Th2 cells
* Allows for selective amplification of cell mediated or humoral immune response
Chemokines Receptor Signaling
Non-Signaling “Silent” Receptors
Structurally unable to elicit migration or activate conventional signaling responses
DARC and D6
* Bind both CXC and CC
* Highly expressed on RBC
* High affinity
* Scavenger receptors which may act as chemokines sink
Functions of Chemokines and Chemokines Receptors
Role of Chemokines in Leukocyte Recruitment
Provide directional cues for movement of leukocytes
* Development, homeostasis, inflammation
Lead to high-affinity integrin-mediated extravasation of leukocytes
Important for homeostatic circulation of leukocytes through tissues
* SDF-1 (CSCL12) is critical for the migration of myeloid precursors from fetal liver to bone marrow.
* Eotaxin (CCL11) recruits eosinophils into tissues
Specific homing signatires (Area Codes) for memory T cells directed for specific sites in tissue
* CCR4-Cutaneus Lymphocyte Antigen 1: SKIN
* CCR9-alpha2beta7 integrin: GUT
Early pro-inflammatory cytokines (IL-1 and TNF-alpha), bacterial products (LPS) and viral infection stimulate chemokine release
Combination of selectin, chemokine and integrin interactions with receptors coordinate recruitment of leukocytes to tissues.
Chemokine Regulation of Leukocyte Movement
CXC Chemokines
Presence or absence of glutamic acid-leucine-arginine (ELR)
Key function of ELR+ CXC chemokines is to attract neutrophils to site of inflammation
* CXCL1, CXCL2, CXCL8
* IL-1, TNF-alpha and LPS elicit production
* Orchestrate early phases of wound healing (angiogenic)
Several ELR are angiostatic
* CXC chemokines (CXCL9, CXCL10, CXCL11) and the receptor they bind (CXCR3)
* All are induced by IFN-gamma.
CXCL8 (IL-8)
- Identififed as neutrophil chemotactic factor
- Induces neutrophil degranulation and respiratory burst
- Facilitates adherence to endothelium
- Induces shedding of L-selectin and regulates expression of integrins of PMN
- Also induces T cell and monocyte chemotaxis
CXCL9, CXCL10 and CXCL11
- CXCL9 and CXCL10 expression induced in macrophage after IFN-gamma stimulation
- Type I IFN can induce CXCL10 but not CXCL9
- TNF induces CXCL9 in endothelial cells
- Bind a common receptor CXCR3
- Involved in chemotaxis of plasmacytoid DCs, NK cells and Th1 cells
- Involved in Th1 mediated immune responses
CXCL12 (SDF-1)
- Bone marrow stromal cells
- Directs migration of hematopoietic cells from fetal liver to bone marrow
- mRNA also found in neuronal, cardiac, vascular and hematopoietic system
- Recruits endothelila progenitor cells (EPC) from the bone marrow.
- Binds CXCR4
- Both CXCR4 and CXCL12 have major role in organogenesis
CXC chemokines receptors
CXCR1 and CXCR2: Expressed mainly on neutrophils
* Bind CXC chemokines with ELR motif
* Involved in early recruitment of leukocytes to inflamed tissues
* Ligans mediate angiogenic activities
CXCR3: Expressed on Th1 cells, NK cells
* Ligands are Non-ELR motif chemokines CXCL9, 10, 11.
CXCR4: Hematopoietic precursor and B pregenitor cells
* Retention of cells in bone marrow and B cell maturation
CXCR5: Expressed mainly on B cells
* Ligans: CXCL13, involved in B migration to Lumphoid follicles
CXCR3
Lignad for CXCL9, CXCL10 and CXCL11
* Induced by IFN-gamma
* Highly expressed during inflammation
Induced receptor expressed primarily on activated Th1, CD8, NK and NKT cells.
* Required for resolution of infection requiring Th1 immunity
* Contributes to pathology in certain autoimmune diseases
CXC Chemokine Receptors
CC Chemokines
- Most numerous and diverse family
- 25 members interacting with 11 receptors
- Have many target cells, mostly hematopoietic cells
- Redundant in their action on leukocytes
- Non-hematopoietic cells include: epithelial cells, fibroblasts, and vascular elements.
- Action of CC chemokine is regulated at the levels of processing and receptor expression.
Functional classification of CC chemokines
MCP
(Mpnocyte Chemotactic Protein)
Five types (MCP1-5)
AKA CCL2, CCL8, CCL7, CCL13, CCL12 (mice)
MCP4 and MCP5 (70% homology to eotaxin)
Functions:
* Recruit monocytes to sites of trauma, bacterial, and mycobacterial infection, toxin exposure and ischemia.
* Promote chronic inflammation
* Activate macrophages
* Induce Basophil histamine release
RANTES, MIP1-alpha, MIP1-Beta
- AKA CCL5, CCL3, CCL4
- Produced by endothelial cells, T-cells and platelets
- Constituvely expressed in T cells
- Induces monocyte chemotaxis
- Mitogenic to Tcells (upregulates expression of IL-2R)
- Enhance NK and CTL killing
Eotaxin (CCL11)
- Produced by macrophages, endothelial cells, epithelium, lymph nodes, lung
- Involved in pulmonary allergy
- Shares biological activities of MCPs
- Involved in eosinophil recruitment
- Eotaxin -/- mice; reduction of tissue eosinophilia
CC chemokine receptors
Expressed on NK cells, T cells, macrophages, dendritic cells, basophils , eosinophils
CCR1-CCR5, CCR8 identified first
* CCR1 (MIP1a/RANTES) most promiscuous receptor
* CCR2: Less promiscuous, monocyte recruitment
* CCR3: Receptor for eotaxin (basophils, eosinohils, Th2 cells), involved in allergic formation.
* CCR4: Expressed on Th2 cells
* CCR5: Expressed on Th1 cells, binds MIP-1a, MIP-1b, RANTES
* CCR6/CCR7: expressed on DCs crucial player DC trafficking and activation
* CCR9/CCR10: T-cell development and homing
Chemokines and Cancer Metastasis
- Promote proliferation and survival of tumor cells at the primary lesion
- Promote angiogenesis and remodeling of surronding ECM
- Recruit different tumor promoting and anti-tumor immune cells to primary sites and pre metastatic niches.Tregs, TAMs, MDSCs inhibit anti tumor immunity
- Myeloid immune cells a premetastic niches secrete chemokines that promote angiogenesis and tumor invasion
G-protein coupled receptors and inflammatory diseases
- Chronic inflammatory disease are characterized by the presence of cell infiltrates
- Resolution of inflammation leads to amelioration/resolution of disease process
- Small molecule inhibitors of GPCRs are currently being studied in the treatment of various diseases.
