Collagen-Binding Integrins in the Pathogenesis of Rheumatoid Arthritis

Mohammed-Amine El-Azreqand and Fawzi Aoudjit*

Département de Microbiologie-Infectiologie et d’Immunologie, Laval University, Canada

*Corresponding author: Fawzi Aoudjit, Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, Quebec, QC, G1V 0A6, Canada

Received: January 08, 2014; Accepted: January 13 , 2014; Published: January 17, 2014

Integrins are α/β heterodimeric cell surface receptors, which mediate cell-cell interactions and adhesion to the surrounding extracellular matrix (ECM). T cells express several ECM receptors among which the very late activating antigens (VLA-1 to VLA- 6) that constitute the β1 subfamily of integrins [1-3]. Following T cell activation, these receptors coordinate T cell adhesion and migration through basement membranes and interstitial tissue to reach inflammatory and infectious sites, but can also regulate their activation [1-3]. The collagen-binding integrins VLA-1 (α1β1) and VLA-2 (α2β1) have recently gained more attention as putative regulators of T cell-mediated immunity and inflammation [1,3]. They are expressed only on effector T cells; whereas other ß1integrin’s such as fibronectin and laminin receptors (α4β1 and α5β1; and α3β1 and α6Β1 respectively) are also found on naÏve T cells. α2β1 bindspreferentially collagen I, whereas a1ß1 has collagen IV as a preferred ligand [4-6]. α1β1 and a2ß1integrins were found in human in vitroderived non polarized CD4⁺ and CD8⁺ effector T cells [7], as well as in CD4+ and CD8+ T cells isolated from virus-infected mice [8]. α2β1 integrin is expressed in Th1 but not in Th2 cells [9,10], and we showed that Th17 cells, a more recently described CD4⁺T cell subset, express α2β1 but not α1β1 integrin [11]. Both integrinscostimulate TCRdependent proliferation of non-polarized effector T cells [7] and we and others have shown that they also promote the survival of effector T cells [12-15]. We also found that α2Β1 but not a1ß1costimulates non-polarized effector T cells to produce IFNγ [16]. Along these lines, an earlier study has shown that collagen I (α2β1 ligand) can activate IL-2-dependent synovial T cell clones to produce IFNγ [17]. Interestingly, we found that a1ß1up regulates the production of the osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand (RANKL) by non-polarized effector T cells [18]. Finally, we have recently reported that a2ß1is the major collagen-binding integrin expressed on human effectors Th17 cells [11]. TCR-activation of Th17 cells induces their attachment via α2β1 to collagen I and II, two abundant matrix proteins in the synovium, and both types of collagen co stimulated TCR-dependent IL-17 production [11].

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by a massive infiltration of immune cells to the joints, leading to synovitis, cartilage erosion and bone damage. RA was initially described as a Th1 disease but more recently Th17 cells have emerged as major effectors T cells in RA [19]. Th17 cells have been detected in the synovium of RA patients and their frequency correlated with the severity of RA. Data from animal models also demonstrated the importance of Th17 cells in the pathogenesis of RA. IL-17 stimulates the production of inflammatory cytokines and chemokines such as IL-1, TNFα and IL-6, by macrophages, chondrocytes and fibroblast like synoviocytes (FLS) leading to the recruitment of additional Th17 cells and other inflammatory cells such as neutrophils. IL-17 also stimulates FLS and osteoblasts to produce RANKL, which is critical for the development of osteoclasts; the cells responsible for bone erosion associated with RA(Reviewed in [20]).

The first link between collagen-binding integrins and RA was provided by an early study in which Hemler’s group demonstrated the expression of these molecules in T cells isolated from synovial fluids of RA patients [21]. Other studies have confirmed the expression of a1ß1 integrin in RA synovial T lymphocytes, and that these cells exhibit a partially distinct repertoire of T-cell receptor (TCR), which could be potentially associated with a higher pathogenicity [22,23]. Blockade of α1β1 reduced the severity of anti-collageninduced arthritis [24]. Although this animal model is dependent on monocytes and neutrophils rather than on T cells. Most recently, we reported that synovial Th17 cells from RA patients as well as from collagen-induced arthritic mice express high levels of α2β1 integrin [25]. Blockade of α2β1 with a blocking antibody also reduces the severity of arthritis in mice by reducing Th17 cell activity [25]. In addition, α2 integrin knock-out mice were shown to have reduced arthritis, which is associated with a reduction in FLS activation and production of metalloproteinase [26]. Together these studies suggest that α1Β1 and α2β1integrins regulate tissue damage in the RA synovial microenvironment, which is rich in collagen.

Further understanding of the molecular mechanisms by which these receptors regulate the pathogenesis of RA is likely to lead to the development of new therapeutic avenues in RA and other autoimmune disease.

Collagen-Binding Integrins in the Pathogenesis of Rheumatoid Arthritis

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