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

Abstract

Pulmonary eosinophilia, a hallmark pathologic feature of allergic lung disease, is regulated by interleukin-13 (IL-13) as well as the eotaxin chemokines, but the specific role of these cytokines and their cooperative interaction are only partially understood. First, we elucidated the essential role of IL-13 in the induction of the eotaxins by comparing IL-13 gene-targeted mice with wild type control mice by using an ovalbumin-induced model of allergic airway inflammation. Notably, ovalbumin-induced expressions of eotaxin-1 and eotaxin-2 mRNA in the lungs were almost completely dependent upon IL-13. Second, in order to address the specific role of eotaxin-2 in IL-13-induced pulmonary eosinophilia, we generated eotaxin-2 gene-deficient mice by homologous recombination. Notably, in contrast to observations made in eotaxin-1-deficient mice, eotaxin-2-deficient mice had normal base-line eosinophil levels in the hematopoietic tissues and gastrointestinal tract. However, following intratracheal IL-13 administration, eotaxin-2-deficient mice showed a profound reduction in airway eosinophilia compared with wild type mice. Most interestingly, the level of peribronchial lung tissue eosinophils in IL-13-treated eotaxin-2-deficient mice was indistinguishable from wild type mice. Furthermore, IL-13 lung transgenic mice genetically engineered to be deficient in eotaxin-2 had a marked reduction of luminal eosinophils. Mechanistic analysis identified IL-13-induced eotaxin-2 expression by macrophages in a distinct lung compartment (luminal inflammatory cells) compared with eotaxin-1, which was expressed solely in the tissue. Taken together, these results demonstrate a cooperative mechanism between IL-13 and eotaxin-2. In particular, IL-13 mediates allergen-induced eotaxin-2 expression, and eotaxin-2 mediates IL-13-induced airway eosinophilia.

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

“…It is interesting to note that in that model, the relative level of eosinophils in the lung of eotaxin-1-deficient mice was increased compared with wild-type mice. 32 Our current study describes a mechanism by which airway eosinophilia is regulated by localized expression of the eotaxin chemokines. Notably, CCR3 was required for both airway and peribronchial eosinophilia in our transgenic mice, demonstrating a cooperative mechanism for CCR3 and its ligands in directing the recruitment and localization of pulmonary eosinophils.…”

“…[27][28][29] Activated eosinophils have been shown to be a source of several molecules implicated in tissue remodeling processes, including IL-13-induced transforming growth factor (TGF)-␤ 1 . 30,31 Prior studies have shown that IL-13-induced eosinophil recruitment in the lung airway and lung tissue in an acute model are regulated by eotaxin-2 and eotaxin-1, respectively, 32 but the role of these molecules in regulating other aspects of IL-13-induced pathology has not been addressed.…”

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

“…These results are consistent with previously reported acute models of IL-13-induced airway inflammation (1-4). Administration of IL-13 also induced expression of the mucin gene MUC5AC (2,(34)(35)(36) (Fig. 1C) and increased goblet cell mucus production (assessed by periodic acid-Schiff staining; data not shown).…”

Origin, regulation and physiological function of intestinal oeosinophils

“…The mouse genome was shown to only contain functional eotaxin-1 and eotaxin-2 [59,60]. Under baseline conditions, eotaxin-1 and eotaxin-2 are constitutively expressed in a variety of tissues, with especially high levels in the gastrointestinal tract and thymus [47,60,61].…”