The Relationship Between Allergen-Induced Tissue Eosinophilia and Markers of Repair and Remodeling in Human Atopic Skin

Abstract

Several in vitro studies suggest that eosinophils may play a role in fibrosis, remodeling, and repair processes associated with IgE-mediated hypersensitivity. However, the relationship in vivo, between allergen-induced tissue eosinophilia and markers of repair has yet to be established in human atopic subjects. Using the allergen-induced cutaneous late-phase reaction as a model of allergic inflammation, we have tested the hypothesis that eosinophil-derived TGF-β1 and IL-13 are temporarily associated with myofibroblast formation and deposition of tenascin and procollagen I. Biopsies were taken from atopic volunteers at 1, 3, 6, 24, 48, and 72 h after intradermal allergen challenge and were examined by immunohistochemistry. Following the peak of the late-phase reaction (6 h) there were persisting TGF-β1+ eosinophils, α-smooth muscle actin+ myofibroblasts, tenascin immunoreactivity, and procollagen-I+ cells 24–48 h postchallenge. Direct evidence of generation of repair markers was obtained by coculture of eosinophils and fibroblasts. This resulted in α-smooth muscle actin immunoreactivity that was inhibitable by neutralizing Abs to TGF-β as well as production of tenascin transcripts and protein product. TGF-β1 and IL-13 also induced tenascin expression. We conclude that TGF-β1 and IL-13, provided partially by eosinophils, contribute to repair and remodeling events in allergic inflammation in human atopic skin.

Marked Airway Eosinophilia Prevents Development of Airway Hyper-responsiveness During an Allergic Response in IL-5 Transgenic Mice

“…In mice, eosinophils have been implicated in bleomycin-induced pulmonary fibrosis (41) and ectopic splenic bone formation (42). In human atopic skin, eosinophil-derived TGF-␤1 was also temporally associated with myofibroblast formation and with repair and remodeling events after an allergic response (21). Thus, the roles of eosinophils and eosinophil-derived TGF-␤1 may be more diverse and profound than previously recognized.…”

“…Nonetheless, in the allergen challenge in human airways, the late phase airway narrowing occurs before the peak of eosinophil infiltration, and eosinophils persist after the resolution of airway narrowing (48,49). During a cutaneous allergen challenge in atopic individuals, after the peak of the late phase response, eosinophils are present in the skin (21). Thus, eosinophils and tissue eosinophilia may play a role(s) in resolving inflammation and airway reactivity and in the subsequent airway remodeling during and after the allergic response.…”

“…Indeed, in addition to their conventional effector functions, which are based on the release of lipid mediators and cationic granule proteins, eosinophils may functionally interact with immune cells or interstitial cells by presenting Ags (17) and producing cytokines (e.g., IL-4) and growth factors (e.g., TGF-␤) (18). In particular, the association between human eosinophils and TGF-␤1, a factor involved in immunoregulation and wound healing, has been studied extensively in patients with asthma (19,20) and atopic dermatitis (21).…”

Gastrointestinal Eosinophilia

“…[11] In fact, eosinophil-derived transforming growth factor-β is linked with epithelial growth, fibrosis, and tissue remodeling. [12,13] Eosinophils express MHC class-II molecules, relevant co-stimulatory molecules (CD40, CD28, B7.1 and B7.2) and secrete an array of cytokines capable of promoting lymphocyte proliferation, activation and Th1 or Th2 polarization (IL-2, IL-4, IL-6, IL-12, IL-10). [11,[14][15][16][17] Further eosinophil-mediated damage is caused by toxic hydrogen peroxide and halide acids generated by EPO and by superoxide generated by the respiratory burst oxidase enzyme pathway in eosinophils.…”

Selective suppression of leukocyte recruitment in allergic inflammation

“…Interestingly, the suppression by anti-IL-5 (Blyth et al 2000) or IL-5 gene deletion (Trifilieff et al 2001, Cho et al 2004) of lung tissue eosinophils was associated with an attenuation of tissue remodelling in chronic murine models of repetitive allergen challenge, and with a decrease in the content of TGF β 1 in the lung (Cho et al 2004) was observed. This has also been observed in man: here treatment with anti-IL-5 has been shown to reduce indices of tissue remodelling in allergic reactions in the skin (Phipps et al 2002) and lung . The importance of eosinophils in tissue remodelling has recently been brought into focus in GATA-1 knockout mice lacking eosinophils.…”