Therapeutic inhibition of leukocyte recruitment in inflammatory diseases
Introduction
Several factors, including inflammatory cells, soluble mediators, CAMs, proteolytic enzymes and others, are involved in the pathogenesis of inflammatory disorders. Rheumatoid arthritis (RA) is a chronic musculoskeletal disorder, and a prototype for chronic inflammation, thus, it is chosen here to demonstrate the mechanisms of inflammatory cell recruitment and the possible strategies to target these processes 1., 2., 3.•, 4., 5..
The vascular endothelium is involved in leukocyte recruitment. In inflammatory reactions, endothelial cells are not passive bystanders, but are active responders to external stimuli. These cells also produce cytokines and chemokines, express CAMs and thus actively influence the outcome of the inflammatory response [6].
Leukocyte extravasation into the synovium through the endothelium is mediated by leukocyte and endothelial adhesion molecules. CAMs mediate all steps of leukocyte adhesion and migration 2., 4.. Increased amounts of the following molecules have been detected on various cell types in the RA synovium 2., 4. (Table 1): most integrins; E- and P-selectins; members of the immunoglobulin superfamily, such as intercellular adhesion molecules (ICAM)-1, -2 and -3; vascular cell adhesion molecule (VCAM)-1; platelet-endothelial cell adhesion molecule (PECAM)-1; CD2; lymphocyte function-associated antigen (LFA)-3; CD31; members of the CD66 family and; other CAMs.
Chemotactic cytokines, termed ‘chemokines’, are involved in leukocyte chemotaxis and migration through the endothelial barrier into the inflamed synovium 3.•, 4., 5.. Chemokines have been classified into four distinct supergene families, namely C–X–C, C–C, C and C–X3–C, according to the location of conserved cysteine (C) residues 3.•, 4., 5., 7.. Recent reviews discuss the role of chemokines in RA 3.•, 4., 5., 8. (Table 2). Among C–X–C chemokines, mostly recruiting neutrophils, interleukin-8 (IL-8; CXCL8), epithelial-neutrophil activating protein-78 (ENA-78; CXCL5), growth-related gene product α (groα; CXCL1), connective tissue activating protein-III (CTAP-III; CXCL6) and stromal cell-derived factor-1 (SDF-1; CXCL12) play a major role in the pathogenesis of synovitis 3.•, 4., 5., 9.. By contrast, platelet factor 4 (PF4; CXCL4), interferon (IFN)-γ-inducible protein 10 (IP-10; CXCL10) and monokine induced by IFN-γ (MIG; CXCL9) may suppress synovial inflammation 3.•, 4., 5.. C–C chemokines are chemotactic primarily for mononuclear cells, such as monocyte chemoattractant protein-1 (MCP-1; CCL2), macrophage inflammatory protein-1α (MIP-1α; CCL3), MIP-3α (CCL20) and ‘regulated upon activation normally T-cell expressed and secreted’ (RANTES; CCL5) have also been associated with RA 3.•, 4., 5., 10.. C–X–C chemokines that contain the ELR (Glu-Leu-Arg) amino acid sequence have been implicated in angiogenesis, a process involved in leukocyte ingress into inflammatory sites 5., 11.. The CX3C chemokine, fractalkine (CX3CL1), and the C chemokine, lymphotactin (XCL1) also play a role in arthritis 3.•, 12., 13., 14..
There are several known chemokine receptors, abbreviated as CXCR, CCR, CX3CR and XCR for C–X–C, C–C, CX3C and C chemokines, respectively (Table 3) 3.•, 4., 5.. It has been suggested that these receptors play a different role in various inflammatory reactions; for example, CCR3, and the ligand eotaxin, are mainly expressed by lymphocytes exhibiting the T helper (Th)2 phenotype, as in allergic lymphocytic infiltrates 15., 16.. By contrast, CCR5, present on most Th1 cells, has been detected in the RA synovium. In addition, CXCR3 is present on both Th1 and Th2 cells, and this chemokine receptor is expressed in both allergic and synovial infiltrates 15., 17., 18.. Briefly, among others, CXCR2 [19], CXCR3 15., 17., 18., CXCR4 20.•, 21., CCR1 22.•, 23., 24., CCR2 23., 24., 25., CCR4 23., 26., CCR5 15., 17., 18., 23., 24., 26., CCR6 [10], CX3CR1 [26] and XCR1 13., 14. have been implicated in inflammatory synovitis.
Leukocyte extravasation into inflamed tissues, including synovia, occurs in at least four distinct steps. First, weak adhesion, termed ‘rolling’, occurs within 1–2 h, and is mediated by endothelial E- and P-selectins, leukocyte L-selectin and their ligands. Second, leukocyte activation and triggering occurs, due to the interactions between chemokine receptors on leukocytes and proteoglycans on endothelial cells. Third, activation-dependent, firm α4β1 integrin–VCAM-1 and LFA-1–ICAM-1 interactions occur; intercellular adhesion is accompanied by the secretion of chemokines. Finally, transendothelial diapedesis occurs when secreted chemokines bind to endothelial heparan sulphate glycosaminoglycans. α4β1 and α5β1 integrins recognize endothelial fibronectin, while α6β1 binds to laminin. These adhesive interactions enable leukocyte ingress into the synovium 4., 27.. Apart form CAM expression regulated by chemokines, recent data, discussed later, suggest that reversely, CAMs might also influence chemokine production [28•]. Thus, there is important crosstalk between chemokines and CAM, which may be important in tissue-specific recruitment or ‘homing’ of inflammatory cells 4., 28.•, 29.••.
Possible therapeutic targets in the inflammatory process will be discussed, focusing on the role of CAMs, as well as chemokines, in this context. Chemokine and CAM targeting has recently been reviewed 8., 30.•. Here, more recent data from some human clinical trials, and from studies conducted in animal models of RA will be reviewed (Table 4).
Section snippets
Anti-adhesion molecule targeting
Clinical trials using anti-adhesion therapy have provided an important perspective on the role of cell adhesion and CAMs in the pathogenesis of RA 2., 30.•. Previously, an anti-human ICAM-1 antibody (enlimomab) was used to treat refractory RA. Many patients reported improvements in their status; however, clinical results were only transient 2., 31.. Also, in earlier studies using rat, mouse and rabbit models of RA, anti-ICAM-1 and anti-β2 integrin antibodies, as well as the integrin-ligand RGD
Inhibition of chemokines and chemokine receptors
Targeting chemokines or their receptors might be feasible when designing new approaches to antirheumatic therapy. Non-specific strategies include the use of anti-inflammatory drugs, which may also affect chemokine production. Alternatively, chemokines and their receptors may be targeted directly using specific antibodies or inhibitors 3.•, 4., 5., 8..
In earlier studies, corticosteroids, sulfapyridine and infliximab were shown to suppress interleukin (IL)-8 and MCP-1 production. Anti-IL-8,
Manipulation of chemokine–adhesion molecule crosstalk
As described previously, chemokines are important regulators of CAM expression and function; thus, these ‘homing chemokines’ are involved in inflammatory cell adhesion and migration, as regulated by CAM 3.•, 4., 5., 15.. These interactions might also be targeted in antirheumatic therapy.
Recently, as described here, TAK-779 (an inhibitor of CXCR3 and CCR5) inhibited chemokine-induced LFA-1 activation, as measured in an adhesion assay using microplates coated with purified ICAM-1 [45].
In addition
Summary
Here, we have discussed some recent advances in targeting inflammatory cell recruitment. Arthritis was chosen as a prototype for chronic inflammation. There have been several attempts to block leukocyte ingress into the synovium by the inhibition of chemokines, chemokine receptors and adhesion molecules. Preclinical studies, performed in animal models of synovitis already have been and possibly will continue to be followed by human clinical trials (Table 4). Thus, it can be concluded that
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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