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The eosinophil enigma
Timothy J. Williams
School of Medicine, Imperial College London, London, United Kingdom
Address correspondence to: Timothy J. Williams, Leukocyte Biology Section, Biomedical Sciences Division, School of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, United Kingdom. Phone: 44-020-7594-3159; Fax: 44-020-7594-3119; E-mail: tim.williams@imperial.ac.uk.
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Published February 15, 2004 - More info
J Clin Invest. 2004;113(4):507–509. https://doi.org/10.1172/JCI21073.
© 2004 The American Society for Clinical Investigation
Since the discovery of the eosinophil, a leukocyte with a granular cytoplasm that stains pink with eosin dye, the function of this cell has been disputed; opinions on its role have swung periodically, as it has been characterized alternately as damaging and protective. Eosinophils accumulate in tissues in response to parasitic worm infections and, on activation, release cationic proteins from their granules and reactive oxygen species that are toxic to worms. Allergy may be an aberration of this defense process whereby otherwise innocuous agents in the environment stimulate an adaptive immune response, characteristically driven by Th2 lymphocytes, resulting in the recruitment and activation of eosinophils that induce tissue damage. Eosinophils also release leukotrienes that induce smooth muscle contraction and microvascular leakage. IL-5, produced by Th2 lymphocytes, is critically important in this process, as it mediates the terminal differentiation and proliferation of eosinophils in the bone marrow and their release into the blood. IL-5 also primes eosinophils, for example, to facilitate eosinophil recruitment into tissues mediated by chemokines such as eotaxins, and IL-5 also prolongs eosinophil survival.
The key role of IL-5 in eosinophil production and function has made this cytokine a prime therapeutic target. This has been reinforced by results in animal models of asthma showing that deletion of the IL-5 gene (1) or the use of IL-5–neutralizing antibodies (2) is able to suppress eosinophil recruitment to the lung and, in many but not all cases (3), inhibit hyper-responsiveness of the airways to agents that induce bronchoconstriction, a characteristic feature of allergic asthma. Double eotaxin-1/IL-5 gene–deleted mice exhibited a greater suppression of eosinophil recruitment to the lung and the abolition of airway hyper-responsiveness associated, interestingly, with reduced IL-13 production (4).
Animal studies, particularly those in allergic cynomolgus monkeys showing long-term inhibition of lung eosinophilia and airway hyper-responsiveness by a single dose of an anti–IL-5 antibody (5), encouraged the initiation of clinical trials in which antibody was administered to mild atopic asthmatics (6) and chronic severe asthmatics (7). These studies showed no consistent effects on lung function tests, despite a marked suppression of blood eosinophils. From the results of these studies, some concluded that eosinophils are not causally related to lung dysfunction, although the results are contentious, particularly because of the small size of the trials and their technical limitations (8, 9). Furthermore, a follow-up study of bronchial biopsies from antibody-treated patients showed that despite marked depletion of blood and sputum eosinophils, airway tissue eosinophils were only depleted by 55% (10), suggesting that the residual cells could be important in lung dysfunction.
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The eosinophil in tissue remodeling
The finding that eosinophils are able to produce growth factors directed attention to the potential role of these cells in the resolution of inflammation and tissue repair. Tissue eosinophilia is a characteristic feature of several fibrotic diseases, and these cells are implicated in the remodeling that occurs in allergic asthma. Remodeling manifests itself in the airway wall as an increased deposition of extracellular matrix proteins in the reticular basement membrane and bronchial submucosa, an increase in smooth muscle mass, goblet cell hyperplasia, and angiogenesis. Eosinophils are capable of producing TGF-α, TGF-β1, and VEGF, as well as a range of cytokines, including IL-13.
Evidence from animal models supports the view that eosinophils have an important role in tissue remodeling. An antibody to IL-5 (11) and IL-5 gene deletion (12) have been shown to suppress lung eosinophilia and components of lung remodeling in murine models of allergic asthma. In this issue of the JCI, the study by Cho et al. (13) investigates the relationship between eosinophils and tissue remodeling in detail. They show in a chronic repetitive allergen challenge model that IL-5 gene deletion suppresses lung eosinophilia and tissue remodeling in parallel. Specifically, IL-5–deficient mice exhibited reduced eosinophil numbers in bronchoalveolar lavage fluid (BALF) and in peribronchial tissue. This was associated with decreased TGF-β1 content of lung tissue with evidence that eosinophils were the major source of the growth factor. Interestingly, the epithelial cell expression of αvβ6, the integrin that is upregulated in response to tissue injury and activates latent TGF-β1 (14, 15), was also suppressed. Allergen-induced increase in peribronchial fibrosis, as measured by trichrome staining, collagen III and collagen V immunostaining, and total lung collagen content, was reduced in IL-5–deficient animals. Peribronchial smooth muscle thickness and epithelial mucus expression were also reduced.
These results echo observations made in humans. It has been shown that eosinophil-derived TGF-β1 is associated with the transformation of fibroblasts to myofibroblasts and the expression by these cells of tenascin and procollagen I in allergic responses in human skin (16) (Figure 1). Furthermore, treatment of asthmatic patients with an antibody to IL-5 suppressed bronchial eosinophilia, the proportion of eosinophils expressing TGF-β1, and the levels of TGF-β1 in BALF (17). The expression of tenascin, lumican, and procollagen III in bronchial mucosal reticular basement membrane was also reduced (17).
Figure 1Role of eosinophil-derived TGF-β1 in lung remodeling. Eosinophils in the asthmatic lung release latent TGF-β1. Latent TGF-β1 (latTGF-β1) is activated by αvβ6 expressed on airway epithelial cells. TGF-β1 mediates airway remodeling by inducing the formation of myofibroblasts that secrete extracellular matrix proteins, and the growth factor also stimulates airway smooth muscle hyperplasia.
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