Chemokines: orchestrating cell trafficking

Katalin Szaszi
Katalin.szaszi@unityhealth.to
Keenan Research Center
for Biomedical Science
Associate professor
Dept Surgery University of Toronto
 Inflammation: a “double edged sword”
Tissue damage, injury, infection

Damaging physical
stimuli

Acute
Chronic
Pathogens inflammation
inflammation

Chemicals
Disease
Resolution, tissue repair
 Inflammation:
a coordinated response to tissue damage

Released
chemical
factors

BioNinja
Chemotaxis (i.e. directional migration) is governed by the ability of the cell to sense
a gradient of chemotactic factors

Video: David Rogers,

Vanderbilt University

Chemotactic factors include

-Bacterial products (formylated peptides);
-Various products released from infected cells or immune
cells: antimicrobial proteins; inflammatory-derived lipids
such as leucotriene B4; complement factors

-Chemokines
 Chemokines:
“chemotactic cytokines”: small proteins secreted by cells that influence the
immune system
They induce directed chemotaxis in nearby
responsive cells
-secreted proteins
Classification as a chemokine based on:
a) function
b) structural characteristics:
-low molecular weight (8-11 kDa);
-four cysteine residues in conserved locations,
that are key to forming the 3D-protein structure:
C-terminal α helix, 3 antiparallel β strands
 Function:
chemoattractants to guide the migration of cells.
-bind to and activate a family of G-protein-coupled receptors
-bind to glycosaminoglycans (GAG) (e.g. on endothelial cell surface)

-Homeostatic chemokines: produced and secreted constitutively (no need for

stimulus); crucial for immune surveillance e.g. by directing lymphocyte homing to
lymph nodes (homing)
Roles in development: promote angiogenesis and cell maturation.
-Inflammatory: released from a wide variety of cells in response to infection, injury.
Often stimulated by pro-inflammatory cytokines (e.g. interleukin 1); they are
chemoattractants for leukocytes guiding them to sites of infection, damage. Some
promote wound healing.

by L. Kohidai
 -CLASSIFICATION BASED ON STRUCTURE:
Structurally-related proteins with conserved cysteine residues; C-terminal
α helix, 3 antiparallel β strands

N-term
 CLASSIFICATION BY STRUCTURE:
4 families according to the number and position of the first two N-terminal cysteines
CC chemokines (β-chemokine)
-two adjacent cysteines near N-term
-at least 27 members
-they induce migration of monocytes, lymphocytes, basophils, eosinophils
-e.g. monocyte chemoattractant protein-1 (MCP-1 or CCL2);
CCL5 (or RANTES): attracts T cells, eosinophils and basophils; CCR5 receptor.
CXC chemokines (α-chemokines)
-The two N-terminal cysteines separated by one amino acid ("X").
-17 CXC chemokines
- active mainly on neutrophils
-e.g. interleukin-8 (IL-8)
C chemokines (γ chemokines)
-only two cysteines; one N-terminal cysteine and one cysteine downstream.
-2 members
CX3C chemokines (d-chemokines)
-3 amino acids between the two cysteines (X3)
-Only known member: fractalkine
- both secreted and tethered to the surface: both a chemoattractant and an
adhesion molecule.
 Chemokine Receptors Structure

- structurally related

- Most are G protein coupled

- 7 transmembrane (7TM) glycoproteins

- variable N-terminus determines

chemokine binding specificity
-
- variable C-terminus determines
interactions with signaling molecules
 Chemokine Receptors
Expressed predominantly on leukocytes

Classification
1. Specific
- bind only one specific chemokine e.g. CXCR1; CXCR4

2. Shared
- bind several chemokines within the same branch
e.g. CXCR2; CXCR3; CCR1-CCR5

3. Promiscuous
- bind multiple chemokines across branches
e.g. Duffy antigen
Kinashi T (2005), Nat Rev Immunol, 5: 546-559
Chemokine/ Chemokine Receptor Family
Emerging role of chemokines and their receptors in diseases