ELR⁺ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets

Abstract

ELR⁺ CXC chemokines, by direct interaction with their cell surface receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2), are believed to be crucially involved in the direct migration and activation of leukocytes.

ELR⁺ CXC chemokines are supposed to play a key role in several inflammatory diseases and this makes ELR⁺ CXC chemokines and their receptors attractive therapeutic targets.

The first aim of this review is to discuss the potential pathological role of ELR⁺ CXC chemokines in different pathologies, including ulcerative colitis (UC), ischaemia/reperfusion injury (RI), bronchiolitis obliterans syndrome (BOS) and tumor progression.

Moreover, the most recently described inhibitors of ELR⁺ CXC chemokines and their therapeutic indications will be reviewed.

Finally, the mode of action and the potential therapeutical use of reparixin, a new potent and selective inhibitor of CXCR1/2 activity, and its chemical derivatives are also discussed.

Introduction

Among chemotactic factors, chemokines are relatively small proteins (8–10 kDa) that direct the recruitment of leukocytes from the blood stream to the extravascular tissues (Mackay, 2001). Although this is a normal physiological response designed to fight infection, remove damaged cells and stimulate healing, an uncontrolled recruitment of leukocytes causes tissue damage, slows healing and in some cases may lead to host death. Therefore, inhibition of chemokine-induced biological activities may be an appropriate therapeutic strategy in a number of inflammatory diseases.

Chemokines have been classified into 4 subfamilies, based on the presence of cysteines at the amino terminal: CXC, CC, CX3C and C (Murphy et al., 2000, Gangur et al., 2002). Among chemokine subfamilies, CXC chemokines can be further subclassified into Glu-Leu-Arg (ELR)⁺ and ELR⁻ CXC chemokines, based on the presence or absence of a tripeptide motif ELR at the NH₂ terminus. Interleukin-8 (CXCL8), epithelial neutrophil activating protein (CXCL5), granulocyte chemotactic peptide-2 (CXCL6), neutrophilic activating protein (CXCL7), melanoma growth stimulatory activities (CXCL1, CXCL2 and CXCL3) belong to ELR⁺ CXC subfamily (Murphy et al., 2000). Characteristic of ELR⁺ chemokines is their ability to specifically recruit neutrophil polymorphonuclear leucocytes (PMN) into inflamed tissues. ELR⁺ chemokines-mediated PMN accumulation into sites of inflammation is a multistep process (rolling–adhesion–transmigration) and proceeds as a sequence of overlapping steps that enable cells to exit the blood stream and enter the peripheral tissues. This process occurs as a result of molecular changes on the surface of the endothelium in response to inflammatory stimuli. PMN may process numerous activating signals during rolling, and the transition from slow rolling to arrest occurs as a result of β₂ integrin activation (Constantin et al., 2000). This activation allows high avidity interaction with their ligands on the endothelium, which can be triggered by immobilized ELR⁺ chemokines. Such arrested ELR⁺ chemokines are presented on the endothelial surface and are sufficient to induce PMN arrest from rolling (Rainger et al., 1997).

Two specific receptors for ELR⁺ chemokines, CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2), have been identified on the cellular surface (Holmes et al., 1991, Murphy & Tiffany, 1991). Both receptors bind CXCL8 and CXCL6 with high and similar affinity whereas CXCR2 binds also with ELR⁺ CXC chemokines at high affinity (Lee et al., 1992, Petersen et al., 1994, Ahuja & Murphy, 1996). Although these 2 receptors have been characterized, their roles in mediating biological effects is not well defined. In fact, in vitro studies using anti-receptor monoclonal antibodies and cell lines expressing CXCR1 and CXCR2 have so far led to conflicting evidence as to the role of the 2 receptors in CXCL8-mediated cell chemotaxis (Loetscher et al., 1994, Chuntharapai & Kim, 1995, Quan et al., 1996, Ben-Baruch et al., 1997). However, increased evidences indicate that CXCR1 could have a dominant role in mediating CXCL8 chemotaxis of PMN that express both CXCL8 receptors (Hammond et al., 1995, Bertini et al., 2004, Di Cioccio et al., 2004).

On the other hand, CXCL8-stimulated keratinocyte proliferation and angiogenesis is supposed to be mainly mediated by CXCR2 activation (Addison et al., 2000).

This review focuses on the pathophysiological role played by ELR⁺ CXC chemokines on development of several pathologies including ulcerative colitis (UC), reperfusion injury (RI), bronchiolitis obliterans syndrome (BOS) and tumor progression.

Moreover, the most recent indications and therapeutic use of ELR⁺ CXC chemokine inhibitors, including neutralizing antibodies and small organic molecules, in preventing inflammatory disease progression is also discussed.