The role of IL-4Rá in Nippostrongylus brasiliensis-induced chronic lung pathology

Includes bibliographical references (leaves 108-126).Infection by the parasitic nematode Nippostrongylus brasiliensis involves migration through the lungs, causing significant damage and generating chronic lung pathology. The resolution of N. brasiliensis infection and also the induction of pulmonary pathology, including goblet cell hyperplasia and acute airway inflammation, depend on IL-4Rá signalling. A key feature of IL-4Rá signalling is the induction of a strong TH2 response which induces the development of alternatively activated macrophages (AAMs). AAMs are associated with tissue remodelling and the control of exacerbated inflammation. In order to investigate potential roles for IL-4Rá in N. brasiliensis' induced lung pathology, we infected mice deficient for IL-4Rá on macrophages and neutrophils (LysMCreIL-4Rá-/lox), IL-4Rá -/- and control mice (IL-4Rá-/lox) with N. brasiliensis and examined lung pathology at days 5, 42 and 180 post infection (p.i.).All three mice strains showed similar emphysemic-like pathology (alveolar dilatation) and airway hyperresponsiveness (AHR) which was well developed by day 42 p.i. and remained chronic. However, LysMCreIL-4Rá-/lox mice consistently demonstrated earlier and increased pulmonary inflammation when compared to IL-4Rá-/lox control mice and IL-4Rá-/- mice. Immunological studies at day 5 p.i. revealed that there were increased CD4+ and CD8+ T-cell numbers and increased CD4+ IL-4 and IL-13 production in the lungs of LysMCreIL-4Rá-/lox mice when compared to control and IL- 4Rá-/- mice. LysMCreIL-4Rá-/lox mice also showed decreased pulmonary arginase activity, indicative of a reduction of AAMs. RNA transcript analysis of isolated alveolar macrophages showed a strong association with promoting inflammation in LysMCreIL-4Rá-/lox mice. Together these data demonstrate that IL-4Rá-responsive macrophages control pulmonary inflammation and play an important protective role in the lung following N. brasiliensis infection