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CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
CHEMOKINES IN INFLAMMATION
I.
INTRODUCTION
Fig. 1. Chemokine and chemokine receptor diversity. The chemokines that
can bind to each receptor (indicated as circles) is shown. The chemokine
receptor GPR-2 is now called CCR10, a receptor for both CTACK and for the
mucosal epithelial chemokine MEC (CCL28).
Chemotactic cytokines or chemokines constitute a large family of
highly conserved proteins that act through G-coupled receptors to
regulate diverse biological processes, including hematopoiesis,
leukocyte trafficking and organogenesis. In addition, there are some
situations in which medically important pathogens, including HIV-1,
exploit or subvert the chemokine system. Thus, chemokines are both
beneficial in host defense against infectious agents and potentially
harmful in disease; however, actual clinical roles in these areas are
only recently emerging. This lecture will focus on the role of
chemokines in directing the trafficking of leukocytes, both in normal
immunity as well as in pathologic inflammation. We will also discuss
the potential for targeting specific chemokines and chemokine
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
receptors for therapeutic utility in both inflammation and infectious
disease.
II.
WHAT ARE CHEMOKINES?
Fig. 2. Three-dimensional structure of a prototype CC chemokine. The monomeric
structure of chemokines are very similar and comprise a critically important NH2terminus, three anti-parallel -strands forming a “Greek key” structure connected by
loops and a COOH-terminal -helix (from Sayle & Milner-White, Trends Biochem Sci.
20:374, 1995).
Chemokines are single polypeptide chains of 70-100 amino acids
(molecular weight: 8 to 14 kDa) with a unique, highly conserved
pattern of cysteines in the primary sequence (Fig. 2). The two main
subfamilies, CC and CXC, are distinguished according to the position
of the first two cysteines, which are adjacent (CC) or separated by
one amino acid (CXC). Two additional chemokines do not fit this
scheme, the C chemokine lymphotactin, and the membraneanchored CX3C chemokine fractalkine/neurotactin (see Figures 1-4).
Chemokines bind and signal through a subfamily of G-proteincoupled receptors (GPCRs) (Figure 3). Many of the receptors are
shared (i.e. they bind more than one chemokine), though some are
ligand specific (i.e. they bind only one chemokine).
Despite
considerable promiscuity in the binding of ligands by many of the
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
chemokine receptors, receptor specificity usually does not cross
C/CC/CXC/CX3C boundaries and therefore have been grouped
accordingly.
Six CXC receptors
(CXCR1-6) and eleven CC
receptors (CCR1-11) have been identified along with the lymphotactin
(XCR-1) and fractalkine/ neurotactin (CX3CR-1) receptors. There
are also a number of “orphan” receptors that have significant
similarity to chemokine receptors, but for which the ligands and
biological functions are not known (Figure 1).
Fig. 3. Chemokine receptor-signaling pathways. Chemokine receptors are
coupled to heterotrimeric G-proteins or GPCRs. These receptors contain seven
transmembrane regions giving rise to three extracellular loops and three
intracellular loops. Signaling is accomplished though coupled to heterotrimeric
G proteins. Upon chemokine binding, GTP replaces GDP on G; the G
trimer dissociates, and G and G independently activate downstream effectors
such as adenylate cyclase, phospholipase C, phosphatidylinositol-3-kinase small
GTPases of the rho family involved in cell shape and motility, and protein
tyrosine kinases, which ultimately trigger events such as adhesion and
chemotaxis.
There are examples of highly restricted receptor usage.
For
example, BLC binding only to CXCR5. However, some chemokines
are highly promiscuous in receptor usage, such as RANTES which
signals through CCR1, CCR3 and CCR5 (Fig. 1).
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
The tables below give an overview (simplified) of a few key
chemokines and briefly outline the receptor usage, responsive cells
and in vivo function of these chemokines and receptors
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
Fig. 4 (8.13 Parham). Properties of some chemokines. Chemokines are often
divided into two major groups based on whether there are one (CXC) or no
amino acids (CC) between the first two cysteine residues. Lymphotactin and
fractalkine are the sole representatives of two additional families of C and CX3C
chemokines, respectively.
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
Additional chemokines discussed in this lecture:
produced
attracts
putative
class
name
receptor
by
cells
effect
CXC
BLC
CXCR5
B cell follicle
B cells
organization of
B cell follicles
CC
TECK
CCR9
Ag-activated T cells
recruitment of T cells
(T follicular helpers)
for B cell help
thymus
CD4-CD8- T cells
T cell development
gut
7+ memory T cells*
recruitment of T cells
to mucosal tissue
CC
CTACK
CCR10
keratinocytes
CLA+ skin-homing
memory T cells
recruitment of CLA+
T cells to skin
to mucosal tissue
CC
MEC
CCR10
mucosal epithelium IgA plasmablasts
recruitment of IgA
Plasma cells
CHEMOKINES PLAY A KEY ROLE IN IMMUNE SURVEILLANCE AND
INFLAMMATION.
Lymphocyte recirculation is the process whereby lymphocytes or
other leukocytes undergo repetitive cycles of migration from the blood
into the tissue and back into the vasculature. T cells and B cells NK
undergo continuous recirculation even in the absence of injury or
inflammation as part of normal immune surveillance. (See Lecture 5).
Superimposed on this is ‘recruitment’ of immune cells to inflammatory
sites. The anatomic location and the nature of the inflammatory
stimulus determine which leukocytes migrate to an inflammatory site;
recruitment includes cells that do not recirculate such as neutrophils,
eosinophils and monocytes, as well as some effector T cells.
Chemokines and their receptors are generally accepted to be central
regulators of leukocyte recruitment. Many publications continue to
quote the early notion that the CC receptors effect the migration of
monocytes, eosinophils, basophils, and T cells, whereas CXCR1 and
CXCR2 (IL-8 receptors) effect the migration of neutrophils. In fact,
this early notion that all of the CXC ligands are poor lymphocyte
chemoattractants turns out to be false; CCR7 ligands are robust
attractants for naive B and T cells and for most circulating memory T
cells, CXCR3 ligands are chemotactic for many memory and
activated T cells and NK cells and IgG plasmablasts, and CXCR4
ligands attract most but not all leukocyte types, CXCR5 ligands are
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
chemoattractants for subsets of lymphoid organ-associated (central
memory) T cells and for almost all B cells through the stage of
differentiation into antibody secreting cells, etc.
III.
BASIC MECHANISMS OF LEUKOCYTE RECRUITMENT
As discussed previously and shown in below in Figure 3, recruitment
of leukocytes into the tissue is the result of sequential, independently
regulated receptor-ligand interactions. Each step potentially requires
unique receptor-ligand pair interactions. Thus far, only the selectin
family (L-, P- and E-selectin) and the 4 integrins have been shown
to mediate initial contact (tethering) of cells flowing in the circulation.
Interaction of the cell with these receptors results in the cell ‘rolling’
along the vessel wall. This is followed by rapid (within seconds)
‘triggering’ of integrin-mediated arrest, in which the cell stops rolling.
This arrest involves pertussis-toxin-sensitive Gi protein-linked
receptors. This arrest is spontaneously reversible (in minutes) unless
further signals lead to transmigration through the endothelium
followed by migration into the surrounding tissue.
Fig. 5. The multistep model of lymphocyte-endothelial cell recognition and
recruitment of lymphocytes from the blood (adapted from Butcher and Picker,
Science 272:60-6, 1996)
The physiologic ‘triggers’ of integrin activation are now believed to be
chemokines in most instances, although other GPCR ligands can
also mediate this event. A subset of chemokines trigger integrin-
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
mediated adhesion to the endothelium under fluid flow conditions.
Many chemokines display specific, low affinity binding to matrix
glycosaminoglycans (GAGs) through basic residues on their nonreceptor-binding face. This helps confine and focus chemokine
display on the endothelium. Chemokines are also thought to provide
gradients or ‘trails’ providing navigational orientation within the tissue.
V.
SOURCES AND TARGETS OF CHEMOKINES
Since chemokines are involved in directing cellular trafficking, clearly
the location of expression and/or presentation of chemokines are
critical for their function. Most chemokines are produced by multiple
cell types, but some are produced by only one or two cell types.
Some are produced constitutively, others must be induced, and some
are produced both constitutively and inductively, depending on the
cell type. Many are up-regulated by pro-inflammatory cytokines such
as tumor necrosis factor (TNF-) and interleukin-1 (IL-1) while others
are up-regulated specifically by interferon gamma (IFN-). So how
does it all come together to direct leukocyte trafficking in vivo?
A leukocyte at a given point in its maturation or activation status
expresses a specific set of chemokine and homing receptors. A
given tissue, such as an allergic lung or patch of skin recently
exposed to allergen, or an arthritic joint in a patient with rheumatoid
arthritis, expresses a unique set of vascular addressins (adhesion
molecules) and chemokines. The tissue is able to recruit the subset
of circulating cells bearing the set of adhesion and chemokine
receptors that ‘match’ the available adhesion ligands and
chemokines. Clearly, since each of the receptors and ligands can be
selectively expressed on leukocytes and endothelial cells, the number
of possible combinations is very large – leading to the exquisite
specificity of leukocyte trafficking and recruitment observed in vivo.
The bottom line is that the key to selective recruitment of leukocytes
is their binding to a particular combination of receptors for selectins,
integrins, and chemokines (a sort of molecular zip code).
Subsequently, exposure to chemokine gradients allows precise
navigation and orientation of the leukocytes within the tissue.
As for recruitment from the blood, cell localization within tissues can
also be combinatorially determined….in this case by the particular
combination of chemokine recpeotrs the cell expresses. In an tissue
where multiple ligands are expressed by different cells or
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
microenvironments , cells can engage one attractant gradient after
another, depending on their receptor repertoire. This allows step by
step control of positioning in tissues, and permits refined control of
microenvironmental localization.
VI.
THE IMPORTANCE OF CHEMOKINES IN CELL RECRUITMENT:
AN EXAMPLE
Dust, pollens, and other allergic triggers cause epithelial cells of the
respiratory tract to produce eotaxin. Eotaxin binds to the CCR3
receptor on Th2 cells recruiting them to this tissue. Th2 cells in turn
produce IL-4 and IL-5, and amplify the original effects on epithelial
cells (and mast cells) resulting in production of more eotaxin. Eotaxin
then recruits and stimulates degranulation of eosinophils and
basophils and stimulates mast cells. Recruited eosinophils and Th2
cells produce additional IL-4, IL-5 and eotaxin, which perpetuate the
cycle (Fig. 6).
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
Fig. 6. Eotaxin is a CC-chemokine that plays a critical role in the
development of allergic disease. Allergen-induced triggers cause epithelial
cells to produce eotaxin. Eotaxin recruits Th2 cells that in turn produce IL-4 and
IL-5, and amplify the original effects on epithelial cells (and mast cells) resulting
in production of more eotaxin. Eotaxin then recruits and stimulates degranulation
of eosinophils and basophils and stimulates mast cells. Recruited eosinophils
and Th2 cells produce additional IL-4, IL-5 and eotaxin, which perpetuate the
allergic response. (Actually, CCR4 and its ligands TARC and MDC might be a
better example of attractant implicated in amplifying Th2 responses.
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
Fig. 7. Interferon gamma-induced chemokines play a key role in Th1-type
responses: chemokine participate in amplification loops. IFN- is a product
of activated NK cells and Th1 T cells. IFN- upregulates IP-10, MIG and ITAC in
monocytes and endothelial cells resulting in recruitment of both NK and Th1 T
cells – providing a second example of central involvement of chemokines in
recruitment and maintenance of immune responses.
Monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha
chemoattractant (I-TAC), and IFN--inducible protein of 10 kDa (IP10) are related members of the CXC chemokine subfamily that all
specifically bind to a common receptor, CXCR3 (Fig. 7). As their
names suggest, all are induced by interferon gamma (IFN-), a Th1type proinflammatory cytokine. CXCR3 is expressed by almost all
lymphocytes (effector Th1 cells, NKT cells NK cells) that express
IFNg. Thus, upregulation of these chemokines by IFN- may be an
important mechanism for selective recruitment of activated/effector
cells which can amplify the INFg/Th1 response by further recruitment
of IFNg producing cells.
It is important to note that there are many overly simplified
paradigms in the literature. One is that CXCR3 is selective for Th1
cells. In fact the situation is much more complex. Although almost all
Th1 cells express CXCR3, so do many IL4/IFNg co-producing cells
and even some Th2 cells, as well as IgG plasmablasts. Similarly,
CCR4 is expressed by almost all IL4 producing T cells, but as many
Th1 as Th2 cells (in absolute numbers ) also express it, and it also
functions as a diferetiating homing recpetor for systemic sites (esp
skin) vs. instestines (where there are few detectable CCR4+ T cells).
We will also mention the fact that CCR7 is on all naïve, but also on
most memory and the majority of effector memory cells as well; again
the truth in conflict with widely held beliefs. (see also below)
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
VII.
CHEMOKINES AND HOMEOSTASIS
Chemokines are often thought of as “proinflammatory cytokines”;
however, it is increasingly clear that chemokine-receptor interactions
are also critical for homeostatic functions within the immune system.
Chemokines, for example, are important for establishing and
maintaining the complex architecture of secondary lymph nodes.
Here we will focus on the chemokine ‘map’ in the secondary lymphoid
tissue that directs trafficking/recruitment and microenvironmental
localization of the three major participants in acquired immune
responses: dendritic cells, T cells and B cells (Fig. 8).
Fig. 8. Chemokines provide a map of the lymph node and direct trafficking
of T cells, B cells and dendritic cells.
Antigen-bearing, mature dendritic cells, which express CCR7, migrate
into the lymph nodes and localize in the T cell zones. Dendritic cells
first localize in these zones by the interaction of CCR7 with
SLC/6Ckine expressed by the afferent lymphatics, and then by the
interaction of CCR7 with SLC/6Ckine and ELC/MIP-3 expressed in
the T cell zone. SLC/6Ckine, which is expressed on the high
endothelial venue (HEV), also mediates recruitment of naïve T cells,
which express CCR7, within HEV. This triggers firm adhesion of
naive T cells within the HEV. Thus, the CCR7 ligands help direct
migration of mature DCs and naive T cells to the T cell zone to
enhance DC/T cell interaction.
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
BLC is expressed by stromal cells in B cell follicles and acts to recruit
and organize B cells into follicles. Antigen binding by T cells
upregulates CXCR5 (and down-regulates CCR7) and promotes T cell
migration into the B cell follicle where they to help initiate T–
dependent antibody responses
Thus, the CCR7 and CXCR5 ligands play key roles in the recruitment
and organization of T, B and dendritic cells within the lymphoid
organs.
Immature dendritic cells
express:
CCR1, CCR5, CCR6 and CXCR1
Mature dendritic cells
express:
CCR7
Fig. 9. Maturation of dendritic cells results in profound changes in
responsiveness to chemokines.
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
Immature DC in the tissue express inflammatory chemokine
receptors, including CCR1, CCR5, CCR6 and CXCR1, which may
participate in DC recruitment to inflamed tissues (Fig. 9, above).
Upon stimulation by TNF, CD40L or LPS they lose sensitivity to the
ligands for CCR1, CCR5, CCR6, CXCR1, and upregulate CCR7
expression and function.
As suggested above, chemokines appear to play a role in the antigen
delivery side of this equation as well. Dendritic cells arise from bone
marrow progenitors and migrate via the blood to peripheral tissues
where they reside as “immature” sentinels specialized for antigen
capture but are unable to stimulate T cells. Upon antigen uptake and
stimulation by LPS, TNF or CD40L, they undergo a maturation
process marked by upregulation of molecules required for T cell
activation and gain the ability to migrate to the CCR7 ligands
SLC/6Ckine and ELC/MIP-3. SLC/6Ckine is expressed by the
endothelial cells lining the lymphatic vessels leading into the lymph
node, and both SLC/6Ckine and the alternative CCR7 ligand MIP-3
are expressed in the T cell zone of lymph nodes and spleen
suggesting a key role in recruitment of mature DC to the T cell zone.
In fact, the dendritic cells in mice deficient in CCR7 ligands fail to
migrate into the draining lymph nodes upon antigen capture and
stimulation.
Thus, SLC/6Ckine (CCL21) appears to play a key role in the
recruitment of both naive T cells and antigen-bearing mature
dendritic cells to the specialized microenvironment required for
T cell priming.
VIII. SPECIFIC MEMORY T CELL SUBSETS TRAFFIC SELECTIVELY
Unlike naive T cells, which recirculate homogeneously (nonselectively) through secondary lymphoid tissue, the homing behavior
of memory/effector T cells is extremely heterogeneous. Distinct
memory/effector subsets display restricted, often tissue-selective
patterns of recirculation. In addition, memory/effector T cells can
enter and recirculate through extralymphoid immune effector sites,
such as the intestinal lamina propria, inflamed skin, joints, and the
pulmonary interstitium.
The tissue-selective trafficking of memory/effector T cell subsets is
partially explained by expression of adhesion molecules, such as
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
cutaneous lymphocyte antigen (CLA) on skin-homing T cells and
a4b7 integrins on gut-homing T cells (Figure 10, below).
It was long hypothesized but only recently shown that specific
chemokine receptors that are expressed on these lymphocyte
subsets interact with specific chemokines that are selectively
expressed in the target tissue. For example, CCR9 is expressed on
resident intestinal intraepithelial lymphocytes, lamina propria T cells
and on discrete subsets of T cells that traffic to intestinal sites. The
ligand for CCR9 is TECK. TECK is expressed in the small intestine,
inducing chemotaxis of these cell populations. This suggests that this
chemokine/receptor pair contributes to the lymphocyte trafficking in
mucosal immune responses.
Fig. 10. Chemokine receptor expression in naive and memory T cells
Similarly, skin-homing CLA+ memory T cells selectively respond to
TARC and a novel chemokine CTACK (cutaneous T cell attracting
chemokine). TARC is expressed on vessels in the inflamed skin and
is thought to bind CCR4 to trigger firm arrest of skin-homing cells and
CTACK, which is expressed by the epidermal keratinocytes, may act
to attract the T cells out of the vessel and into the dermis and
epidermis.
The immune system can construct many specific homing
pathways. This is achieved by varying the expression of homing
and chemokine receptors and their endothelial and tissue
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
counter-receptors. These interactions occur sequentially in a
highly regulated fashion.
IX.
EFFECTS OF ACTIVATION ON THE
CHEMOKINE RECEPTORS ON T CELLS
EXPRESSION
OF
As you already know, Th1 cells express IFN- and are responsible for
directing cell-mediated immunity but may also cause disease of the
immune system, such as organ-specific autoimmune disease. Th2
cells express IL-4 and IL-5, are important in directing humoral
immunity, and are implicated in allergic inflammation. When CD4 T
cells differentiate into Th1 versus Th2 cells, they also acquire distinct
homing phenotypes. Their homing properties seem to be determined
in correlation with their cytokine production programs, and also with
their tissue site of antigen exposure.
CXCR3+ T cells
CCR4+ T cells
skin
homing
T cells
IFN-g
IL4
Th2
Th0
Th1
human blood CD4 memory cells
Figure 12: Overlapping patterns of chemokine receptor, cytokine and skin
homing phenotypes in human blood CD4 subsets. The widespread belief that
CXCR3 is specific for Th1 and that CCR4 is specific for Th2 cells is clearly
misleading. In particular, most CCR4 cells and many CXCR3 cells are ‘nonpolarized’, failing to produce either cytokine. Moreover, CCR4 is highly
expressed by almost all skin homing CD4 cells in human blood (and skin), and
these include both Th1, Th2 and Th0 (IL4+IFNg producing) cells, as illustrated.
This can be taken as an example of the general statement that the
homing properties (combination of adhesion and chemoattractant
receptors) expressed by any T or B cell seem to correlate both with
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
the cells function in a classical sense (Th1, Th2, B helper CD4 cell;
effector vs memory CD8; IgG vs IgA ASC, etc), and with the tissue
site where it was generated in response to antigen. It is likely that
specialized dendritic cell subsets play a major role in determining the
function and homing of antign-activated lymphocytes.
Blood Th1 cells and Th2 cells express overlapping but distinctive sets
of chemokine receptors. (Fig. 12).
Expression of chemokine receptors by
in vivo polarized Th1 or Th2 cells
Th2 cells
%Chem. Receptor+
Th1 cells
Fig. 12. Differential expression of chemokine receptors on Th1 versus Th2
effector cells
X.
CHEMOKINES DO MORE THAN ATTRACT LEUKOCYTES.
Chemokines and their receptors have now been shown to have
additional important functions that extend beyond the regulation of
leukocyte migration. CXC chemokines can also influence endothelial
migration, and function as angiogenic/angiostatic factors. This has
important implications for tumor growth and neovascularization. In
smooth muscle cells, chemokines such as IP-10 and IL-8 can
modulate proliferation and migration. MCP-1 can induce procoagulant
activity that may enhance thrombosis in atherosclerotic plaques.
Also, as described above, eotaxin synergizes with IL-5 to rapidly
mobilize eosinophils from the bone marrow and also induces
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
myelopoiesis. Targeted disruption of the SDF-1 gene (SDF-1
knockout mice) leads to a severe reduction of myeloid progenitors in
bone marrow and absent B cell lymphopoiesis. These findings
suggest a key role for SDF-1 in hematopoiesis.
XI.
CHEMOKINES AND INFLAMMATION
Early evidence for the role of chemokines in disease was
circumstantial, generally based on observations of upregulation of
certain receptors or ligands during the disease. For example, as
illustrated in Figure 4, in human asthma and models of airway
inflammation increased levels of eotaxin and its receptor are
observed. Similarly, RANTES and the IFN--induced chemokines IP10 and MIG are elevated during attacks of multiple sclerosis. Their
receptors (CCR5 and CXCR3) are present in the inflammatory cell
infiltrates. In fact, most infiltrating T cells in diverse inflammatory
sites (outside of blood or lymphoid tissues) express both CXCR3 and
CCR5.
These data, however exciting, do not formally prove that these
chemokines induce the damage. To distinguish causation from mere
association, many investigators are turning to immunologically and
genetically manipulated mice and mouse models of human disease.
There are already some interesting early results suggesting that,
indeed, targeting chemokines may allow us to manipulate the
immune response. For example, IL-8 has been closely associated
with neutrophil-mediated inflammatory disease, e.g. bacterial
pneumonia and ischemia-reperfusion injury. Neutralization of IL-8 in
rabbits affords almost complete protection from multiple inflammatory
challenges, including lung ischemia-reperfusion injury, pleuritis, and
glomerulonephritis.
In addition, the CC chemokine MIP-1 has been shown to be present
in pathologic specimens from patients with multiple sclerosis.
Neutralization of MIP-1 protects against induction of the mouse
model of multiple sclerosis, experimental allergic encephalomyelititis
(EAE). An even more compelling example is the finding that CCR2deficient mice have a reduced susceptibility to experimental
atherogenesis, in which monocytes (which express CCR2 and
respond to the potent CCR2 ligand MCP-1) and macrophages play
an important role.
CHEMOKINES IN INFLAMMATION – Eugene Butcher and Leslie McEvoy
XII.
PHARMACOLOGICAL INTERVENTION
Due to their function in vivo, chemokines and their receptors are
obvious targets for pharmaceutical intervention. Many commercial
labs are searching for small molecules that can disrupt either ligandreceptor interaction or receptor signaling in order to block recruitment,
activation or infection of cells. The GPCRs are especially good
targets, since there has been prior success in finding antagonists to
this family of receptors.
XIV. SUMMARY OF MAJOR POINTS
1. Chemokines are a subset of cytokines that play key roles in
homeostasis, inflammation and a host of other pathologies.
2. Certain chemokine/receptor interactions play crucial roles for
homeostatic functions, particularly
a) establishing the architecture of the secondary lymphoid organs
and for efficiently recruiting naive T cells and antigen bearing
(mature) dendritic cells. Thus, chemokines play a key role in
efficient initiation of the immune response.
b) The targeted recirculation of memory and effector cells for gut vs
skin-associated (allowing more efficient immune surveillance, as
well as specialization of immune response modalities such as IgA
in mucosal sites, IgG in systemic tissues).
3. Some chemokines are potent inflammatory mediators that attract
specific subsets of leukocytes to sites of inflammation.
4. Leukocyte subsets display unique adhesion and chemokine receptor
combinations that can be modulated during maturation, differentiation
and activation.
5. Specific routes of migration, precise navigation, and orientation within
the tissue are determined by combinatorial expression of receptors
and sequential encounters with different chemokine gradients.
(Acting in combination with adhesion/homing receptors in the multistep process of recruitment and chemotactic navigation).
6. Chemokine receptor expression is not static. Homing behavior, like
other lymphocyte functions, is tightly controlled. Thus, leukocytes
undergo constant reprogramming of responsiveness to constitutive
and inflammatory chemokines. This reprogramming controls their
capacity to selectively migrate to lymphoid, and inflamed tissues.
CHEMOKINES IN INFLAMMATION —LESLIE M. MCEVOY, PH.D. AND EUGENE BUTCHER
7. A number of syndromes and diseased tissues are marked by
selective expression of certain chemokines that may play key
regulatory roles; thus, chemokines and/or chemokine receptor
antagonists are likely therapeutic candidates (and many are under
current investigation).
Recent References:
1: Kunkel EJ, Butcher EC.
Plasma-cell homing.
Nat Rev Immunol. 2003 Oct;3(10):822-9. Review.
PMID: 14523388 [PubMed - indexed for MEDLINE]
2: Campbell DJ, Kim CH, Butcher EC.
Chemokines in the systemic organization of immunity.
Immunol Rev. 2003 Oct;195:58-71.
PMID: 12969310 [PubMed - in process]