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Cellular and Molecular Immunology > Chemokines and Chemokine Receptors > Flashcards

Chemokines and Chemokine Receptors Flashcards

1
Q

What are chemokines?

A

“Chemotactic cytokines”
First discovered in 1980’s
Polypeptides of similar structures
Orchestrate migration and trafficking of cells to tissue
* Homeostasis
* Inflammation

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2
Q

Structural Characteristics of Chemokines

A

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

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3
Q

Classification of chemokine subclass

A

Based on the number and spacing of the conservred Cys residues in their amino termini
CXC-alpha
CC-beta
C-gamma
CX3C-delta

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4
Q

Structural Characteristics of Chemokines

A

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)

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5
Q

Chemokine Function

A
  • Homeostatic
  • Inflammatory
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6
Q

Chemokine Function

Homeostatic

A

Constitutive
Development of B and T cells in secondary lymphoid organs
Immune surveillance
* Skin and mucosal surfaces express increased levels of chemokines

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7
Q

Chemokine Function

Inflammatory

A

Induced
* IL-1
* TNF-alpha
* IFN-gamma
* Microbial products (LPS)
* Trauna/tissue damage

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8
Q

Chemokine Receptors

A
  • 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
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9
Q

Chemokines Receptors Function

A

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

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10
Q

Chemokines Receptor Signaling

A
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11
Q

Non-Signaling “Silent” Receptors

A

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

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12
Q

Functions of Chemokines and Chemokines Receptors

A
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13
Q

Role of Chemokines in Leukocyte Recruitment

A

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.

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14
Q

Chemokine Regulation of Leukocyte Movement

A
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15
Q

CXC Chemokines

A

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.

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16
Q

CXCL8 (IL-8)

A
  • 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
17
Q

CXCL9, CXCL10 and CXCL11

A
  • 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
18
Q

CXCL12 (SDF-1)

A
  • 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
19
Q

CXC chemokines receptors

A

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

20
Q

CXCR3

A

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

21
Q

CXC Chemokine Receptors

A
22
Q

CC Chemokines

A
  • 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.
23
Q

Functional classification of CC chemokines

A
24
Q

MCP
(Mpnocyte Chemotactic Protein)

A

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

25
Q

RANTES, MIP1-alpha, MIP1-Beta

A
  • 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
26
Q

Eotaxin (CCL11)

A
  • 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
27
Q

CC chemokine receptors

A

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

28
Q

Chemokines and Cancer Metastasis

A
  • 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
29
Q

G-protein coupled receptors and inflammatory diseases

A
  • 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.

Cellular and Molecular Immunology (15 decks)

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