Elemental signals regulating eosinophil accumulation in the lung

Abstract

In this review we identify the elemental signals that regulate eosinophil accumulation in the allergic lung. We show that there are two interwoven mechanisms for the accumulation of eosinophils in pulmonary tissues and that these mechanisms are linked to the development of airways hyperreactivity (AHR). Interleukin-(IL)-5 plays a critical role in the expansion of eosinophil pools in both the bone marrow and blood in response to allergen provocation of the airways. Secondly, IL-4 and IL-13 operate within the allergic lung to control the transmigration of eosinophils across the vascular bed into pulmonary tissues. This process exclusively promotes tissue accumulation of eosinophils. IL-13 and IL-4 probably act by activating eosinophil-specific adhesion pathways and by regulating the production of IL-5 and eotaxin in the lung compartment. IL-5 and eotaxin co-operate locally in pulmonary tissues to selectively and synergistically promote eosinophilia. Thus, IL-5 acts systemically to induce eosinophilia and within tissues to promote local chemotactic signals. Regulation of IL-5 and eotaxin levels within the lung by IL-4 and IL-13 allows Th2 cells to elegantly co-ordinate tissue and peripheral eosinophilia. Whilst the inhibition of either the IL-4/IL-13 or IL-5/eotaxin pathways resulted in the abolition of tissue eosinophils and AHR, only depletion of IL-5 and eotaxin concurrently results in marked attenuation of pulmonary inflammation. These data highlight the importance of targeting both IL-5 and CCR3 signalling systems for the resolution of inflammation and AHR associated with asthma.

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

“…Likewise, exposure of IL-5 gene knockout mice to aerosolized Ags caused an ablated eosinophil recruitment into the lungs (42). The results from both in vitro and in vivo investigations also suggest that eotaxin and IL-5 may act cooperatively and synergistically to promote the recruitment of eosinophils into tissues (29,30,43,44). In mice, eotaxin-induced recruitment of eosinophils to the lung and skin was only consistently observed in IL-5-transgenic mice, which have elevated levels of IL-5 and a pronounced basal blood eosinophilia (29,30).…”

“…The results from both in vitro and in vivo investigations also suggest that eotaxin and IL-5 may act cooperatively and synergistically to promote the recruitment of eosinophils into tissues (29,30,43,44). In mice, eotaxin-induced recruitment of eosinophils to the lung and skin was only consistently observed in IL-5-transgenic mice, which have elevated levels of IL-5 and a pronounced basal blood eosinophilia (29,30). Thus, during the inflammatory response, IL-5 may provide the signal for the release of a pool of eosinophils from the bone marrow, whereas eotaxin may elicit the signal for eosinophil localization to the site of inflammation by up-regulating integrins and stimulating chemotaxis.…”

Identification of a Cooperative Mechanism Involving Interleukin-13 and Eotaxin-2 in Experimental Allergic Lung Inflammation

“…This may reflect the requirement for the up-regulation of both the eotaxins and IL-5 and their synergistic interactions for maximal eosinophilic responses. In particular, IL-5 promotes an expansion of circulating eosinophils in response to antigen provocation, whereas eotaxin subsequently sequesters eosinophils into tissues (15,67). Additionally, IL-5 has been shown to induce CCR3 on eosinophil precursor cells (68).…”

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

“…IL-4 (23), IL-13 (24,25)] and chemokines [e.g. RANTES (26,27)] may further amplify the inflammatory milieu. Thus, the local production of such eosinophil factors may be important in tissue eosinophil reactions beyond IL-5.…”