Decreased Expression of Membrane IL-5 Receptor α on Human Eosinophils: I. Loss of Membrane IL-5 Receptor α on Airway Eosinophils and Increased Soluble IL-5 Receptor α in the Airway After Allergen Challenge

Abstract

IL-5 is a key cytokine for eosinophil maturation, recruitment, activation, and possibly the development of inflammation in asthma. High concentrations of IL-5 are present in the airway after Ag challenge, but the responsiveness of airway eosinophils to IL-5 is not well characterized. The objectives of this study were to establish, following airway Ag challenge: 1) the expression of membrane (m)IL-5Rα on bronchoalveolar lavage (BAL) eosinophils; 2) the responsiveness of these cells to exogenous IL-5; and 3) the presence of soluble (s)IL-5Rα in BAL fluid. To accomplish these goals, blood and BAL eosinophils were obtained from atopic subjects 48 h after segmental bronchoprovocation with Ag. There was a striking reduction in mIL-5Rα on airway eosinophils compared with circulating cells. Furthermore, sIL-5Rα concentrations were elevated in BAL fluid, but steady state levels of sIL-5Rα mRNA were not increased in BAL compared with blood eosinophils. Finally, BAL eosinophils were refractory to IL-5 for ex vivo degranulation, suggesting that the reduction in mIL-5Rα on BAL eosinophils may regulate IL-5-mediated eosinophil functions. Together, the loss of mIL-5Rα, the presence of sIL-5Rα, and the blunted functional response (degranulation) of eosinophils to IL-5 suggest that when eosinophils are recruited to the airway, regulation of their functions becomes IL-5 independent. These observations provide a potential explanation for the inability of anti-IL-5 therapy to suppress airway hyperresponsiveness to inhaled Ag, despite a reduction in eosinophil recruitment.

Cross-Talk between ICAM-1 and GM-CSF Receptor Signaling Modulates Eosinophil Survival and Activation

“…Studies by Bates et al (38) using eosinophils obtained from bronchoalveolar lavage fluid documented a decreased responsiveness of cells to IL-5 stimulation that was paralleled by a decreased expression of the ␣-chain of the IL-5 receptor. These findings were independently confirmed by Liu et al (36,37) who reported distinct regulation of the receptors for IL-3, GM-CSF, and IL-5. In vitro studies showed that 24 h of stimulation of eosinophils with IL-5 resulted in the down-regulation of expression of the ␣-chains of the receptors for IL-5 and GM-CSF and in up-regulation of the ␣-chain of the IL-3 receptor (30).…”

“…In vitro studies showed that 24 h of stimulation of eosinophils with IL-5 resulted in the down-regulation of expression of the ␣-chains of the receptors for IL-5 and GM-CSF and in up-regulation of the ␣-chain of the IL-3 receptor (30). Although these findings suggested a role for IL-3-mediated activated eosinophils in lung eosinophils, further studies showed down-regulation of GMR␤ upon IL-5 stimulation in both in vitro and in vivo models (36,39). Taken together, down-regulation of the GMR␤ receptor that extended beyond 18 h after in vitro stimulation and decreased GMR␤ expression observed in bronchoalveolar lavage eosinophils after segmental allergen challenge suggested the relative independence of late signaling events from cytokine stimulation with GM-CSF, as well as IL-5 and IL-3.…”

“…7A). Because reports of down-regulation of high-affinity receptors (␣-chains) and proteolytic degradation of ␤-chain GM-CSF/IL-5/IL-3 receptor (30,36,37) suggested relative independence of GM-CSFinduced eosinophil activation with constant GM-CSF stimulation, we tested the effect of GM-CSF inhibition on eosinophil survival and compared it with the effect of ICAM-1 blockade. First, we added GM-CSF-neutralizing Ab before and 3 h after GM-CSF stimulation.…”

The NR4A nuclear receptor family in eosinophils

“…On the other hand, a recent study has proved that a significant number of eosinophils exist in the bronchial mucosa in asthmatic patients treated with anti-IL-5 antibody (Flood-Page et al 2002). In support of these findings, Liu et al (2002) have also reported the loss of IL-5 receptor a on airway eosinophils after allergen challenge, which may explain the ineffectiveness of anti-IL-5 antibody. If eosinophil deletion could be achieved by treatment with low molecular weight chemicals, which might penetrate more easily into peripheral inflammatory tissues, the significance of the role of eosinophils would be established, and the controversy would be resolved.…”

The rise of the phoenix: the expanding role of the eosinophil in health and disease

“…The Leckie paper also did not consider IL-5 receptor expression and function of the eosinophils obtained in airway fluid in comparison with blood or tissue eosinophils. Liu et al demonstrated a marked reduction in the expression of messenger RNA of the surface IL-5 receptor (mIL-5Ra) and its intracellular component (mIL-5Rb) from BAL eosinophils compared with blood eosinophils (17). Further, in contrast to circulating eosinophils, BAL eosinophils do not release eosinophil-derived neurotoxin (EDN) when treated with IL-5 as do their blood counterparts, suggesting that the function of BAL eosinophils are IL-5-independent (18).…”