Inhibition of Airway Inflammation by Amino-Terminally Modified RANTES/CC Chemokine Ligand 5 Analogues Is Not Mediated through CCR3

Abstract

Chemokines play a key role in the recruitment of activated CD4+ T cells and eosinophils into the lungs in animal models of airway inflammation. Inhibition of inflammation by N-terminally modified chemokines is well-documented in several models but is often reported with limited dose regimens. We have evaluated the effects of doses ranging from 10 ng to 100 μg of two CC chemokine receptor antagonists, Met-RANTES/CC chemokine ligand 5 (CCL5) and aminooxypentane-RANTES/CCL5, in preventing inflammation in the OVA-sensitized murine model of human asthma. In the human system, aminooxypentane-RANTES/CCL5 is a full agonist of CCR5, but in the murine system neither variant is able to induce cellular recruitment. Both antagonists showed an inverse bell-shaped inhibition of cellular infiltration into the airways and mucus production in the lungs following allergen provocation. The loss of inhibition at higher doses did not appear to be due to partial agonist activity because neither variant showed activity in recruiting cells into the peritoneal cavity at these doses. Surprisingly, neither was able to bind to the major CCR expressed on eosinophils, CCR3. However, significant inhibition of eosinophil recruitment was observed. Both analogues retained high affinity binding for murine CCR1 and murine CCR5. Their ability to antagonize CCR1 and CCR5 but not CCR3 was confirmed by their ability to prevent RANTES/CCL5 and macrophage inflammatory protein-1β/CCL4 recruitment in vitro and in vivo, while they had no effect on that induced by eotaxin/CCL11. These results suggest that CCR1 and/or CCR5 may be potential targets for asthma therapy.

Role of CCR5 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

“…In accord with this broader view, in addition to Th1 cells, CCR5 is expressed on Th2 cells (37,38) and stromal cells (25). In addition, the observation that CCR5 signaling plays a key role in IL-13-induced tissue responses is in accord with and provides a potential explanation for previous reports demonstrating that CCR5-based interventions abrogate fungus and aeroallergen-induced Th2 inflammatory responses (39,40,53) and the observation that the hypofunctional ␦32 CCR5 polymorphism is associated with a decreased risk of asthma in select study populations (41,42).…”

“…However, CCR5 can also be found on Th2 cells (37,38). In addition, interventions that abrogate CCR5 or interfere with its ligand binding have been shown to alter Th2-induced inflammatory responses (39,40), and hypofunctional polymorphisms of CCR5 (CCR5 ␦ 32) have been reported to be associated with a decreased risk of asthma in some populations (41,42). Surprisingly, the role of CCR5 in the pathogenesis of IL-13-induced effector responses at sites of Th2 inflammation has not been investigated.…”

Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice

“…CCL5 and its receptors have also been shown to have detrimental effects during other inflammatory diseases, including acute Con A-induced liver failure (16,17) as well as atherosclerosis and obesity, which share common pathophysiological pathways with liver diseases (18,19). These intriguing actions of CCL5 and the availability of the specific CCL5 receptor antagonist Met-CCL5 (20)(21)(22) render this chemokine particularly interesting for further investigations in human and experimental liver diseases.…”

A small-molecule compound targeting CCR5 and CXCR3 prevents airway hyperresponsiveness and inflammation

“…CHVATCHKO et al [9] reported that the blockage of CCR5 using amino-terminally modified RANTES/CC chemokine ligand 5 analogues led to decreased AI, but did not affect AHR in a mouse model of OVA-induced asthma. In contrast, in the current study, the blockage of CCR5 using TAK-779 significantly inhibited altered respiratory function as well as AI.…”

“…Chemokines play important roles in a variety of inflammatory disease conditions, such as asthma, inflammatory bowel disease, and infectious diseases [5]. In the field of asthma, several chemokines and chemokine receptors, such as eotaxin, RANTES (regulated on activation normal T-cell expressed and secreted), macrophage inflammatory protein (MIP)-1a, monocyte chemoattractant protein (MCP)-1, MCP-5, and CC chemokine receptors CCR1, CCR3 and CCR5, have been suggested to be critical in the development of allergic airway inflammatory response in animal models [3,[7][8][9]. Furthermore, CCR5 and CXC chemokine receptor (CXCR)3 have been reported to be expressed on human lung T-cells [10].…”