Therapeutic inhibition of CXCR1/2: where do we stand?

Abstract

Mounting experimental evidence from in vitro and in vivo animal studies points to an essential role of the CXCL8-CXCR1/2 axis in neutrophils in the pathophysiology of inflammatory and autoimmune diseases. In addition, the pathogenetic involvement of neutrophils and the CXCL8-CXCR1/2 axis in cancer progression and metastasis is increasingly recognized. Consequently, therapeutic targeting of CXCR1/2 or CXCL8 has been intensively investigated in recent years using a wide array of in vitro and animal disease models. While a significant benefit for patients with unwanted neutrophil-mediated inflammatory conditions may be expected from a potential clinical use of inhibitors, their use in severe infections or sepsis might be problematic and should be carefully and thoroughly evaluated in animal models and clinical trials. Translating the approaches using inhibitors of the CXCL8-CXCR1/2 axis to cancer therapy is definitively a new and promising research avenue, which parallels the ongoing efforts to clearly define the involvement of neutrophils and the CXCL8-CXCR1/2 axis in neoplastic diseases. Our narrative review summarizes the current literature on the activation and inhibition of these receptors in neutrophils, key inhibitor classes for CXCR2 and the therapeutic relevance of CXCR2 inhibition focusing here on gastrointestinal diseases.

Keywords: CXCR2; Cancer; Chemokine receptor inhibition; Gut; Inflammation; Neutrophils.

Fig. 1

The Neutrophil. Neutrophils are terminally differentiated leukocytes, around 12 µm in diameter. They are histologically characterized by a “neutral” color (as opposed to basophilic or eosinophilic granulocytes), segmented nucleus, and granules. Granules contain anti-microbial and anti-tissue proteins including myeloperoxidase (MPO), neutrophil elastase (NE), matrix metalloproteases (MMPs), gelatinase and lactoferrin. Their receptor profiles include G-protein-coupled receptors (GPCRs) like CXC-receptors 1 and 2 (CXCR1/2), Formyl-peptide receptors 1 and 2 (FPRs), and Leukotriene B4 receptors (LTB4-R), as well as Fc-receptors, innate immunity receptors like toll-like-receptors 1–9 (TLR1-9), lectins, RIG- and NOD-like receptors, and non-G-protein-coupled cytokine receptors (NGPCR-Cytokine-R) like interleukin 4 receptor or interleukin 1 receptor 1; as well as adhesion receptors like L-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), leukocyte function-associated antigen 1 (LFA-1), Macrophage antigen-1 (Mac-1) [18, 181]

Fig. 2

Role of CXCR1/2 in the Neutrophil Recruitment Cascade. The recruitment of neutrophils is proceeding along a cascade of adhesion and activation steps. Free flowing neutrophils are initially tethered to the endothelial lining via selectins (e.g., E- and P-selectin) and corresponding selectin ligands (e.g., PSGL1 or ESL1) mediating rolling along the endothelium. During rolling, neutrophils receive activation signals, e.g., through selectin/selectin ligand interactions and through binding of chemokines (e.g. CXCL8) to their receptors (e.g. CXCL2). These signals lead to a conformational change of neutrophil-expressed β₂ integrins which further slows down rolling velocity and eventually mediates firm neutrophil arrest. Relevant chemokine receptors on neutrophils are CXCR1 and 2 interacting with chemokine CXCL8 (Il-8, in humans) or CXCL1 (KC, in mice). After firm adhesion, neutrophils undergo postarrest modifications including β2-integrin clustering, spreading, adhesion strengthening, and crawling. Latter is needed for finding a suitable transmigration spot. Finally, the cell exits the vessel through or between the endothelial cells and penetrates the vascular basement membrane to reach the inflamed tissue. Molecules here include VE-cadherin and others [5, 182]. Figure adapted from [183]

Fig. 3

Inhibition of intracellular CXCR1/2 mediated signaling in neutrophils. Binding of CXCL8 to CXCR1/2 leads to inhibition of adenylyl cyclase, and activation of different enzymes including phospholipase D (PLD), phospholipase Cβ (PLCβ), PI3K and Ras. Inhibition of CXCR1/2 activates adenylyl cyclase, and attenuates the activation of the other enzymes, leading to decreased neutrophil activation. For details and references, see text