IL-13 receptor α2 contributes to development of experimental allergic asthma.

IL-13 receptor α2 (IL-13Rα2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13Rα2 generated by alternative splicing in mice, but human subjects express only the membrane form of IL-13Rα2 (memIL-13Rα2). We determined the role of memIL-13Rα2 in the development of allergic inflammation in mouse models of asthma. IL-13Rα2-deficient and memIL-13Rα2 lung epithelium-specific transgenic mice were challenged with house dust mite (HDM). Airway hyperresponsiveness (AHR) and inflammation were assessed based on the airway pressure-time index, bronchoalveolar lavage (BAL) cell counts, and lung histology. Mucus production was determined by means of periodic acid-Schiff staining of lung sections, Western blot analysis of chloride channel calcium activated 3 (CLCA3) expression in lung homogenates, and ELISA of Muc5ac in BAL fluid. The expression of cytokines and chemokines was determined by using RT-quantitative PCR. In IL-13Rα2-deficient mice AHR and airway inflammation were attenuated compared with levels seen in wild-type mice after HDM challenge. Lung epithelial overexpression of memIL-13Rα2 in the IL-13Rα2-deficient mice reconstituted AHR and inflammation to levels similar to those observed in HDM-challenged wild-type mice. Mucus production was attenuated in lungs from HDM-treated IL-13Rα2-deficient mice, whereas lung epithelial overexpression of memIL-13Rα2 increased mucus production. Lung epithelial overexpression of memIL-13Rα2 had no effect on levels of the soluble form of IL-13Rα2 in serum or BAL fluid and did not affect IL-13-dependent signal transducer and activator of transcription 6 activation in the lungs. These data collectively support a distinct role for memIL-13Rα2 in the lung and suggest that memIL-13Rα2 might contribute to allergic inflammation.

Chen W ，Sivaprasad U ，Gibson AM ，Ericksen MB ，Cunningham CM ，Bass SA ，Kinker KG ，Finkelman FD ，Wills-Karp M ，Khurana Hershey GK ... -  《-》

The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma.

Several clinical and experimental studies have implicated IL-33 and its receptor ST2 in the development of asthma. However, the effect of IL-33/ST2 signalling on airway responses and inflammation in allergic asthma is not well established. To investigate the role of IL-33/ST2 signalling in promoting allergen-induced airway hyperresponsiveness (AHR), airway inflammation, antigen-specific IgE production and mast cell activity in a mouse model of asthma. ST2-deficient (ST2(-/-)) mice and control BALB/c mice were given house dust mite (HDM) extract over a 6-week period. Forty-eight hours after the final HDM administration, lung function and airway inflammation were evaluated. Airway responsiveness was determined in the central airways and peripheral lung. Cellular infiltration and mast cell protease mMCP-1 levels were quantified in bronchoalveolar lavage fluid (BALF). Recruitment of inflammatory cells and inflammatory cytokine profiles were assessed in pulmonary tissue, and HDM-specific IgE was measured in serum. ST2 deficiency diminished HDM-induced AHR in the peripheral lung, while AHR in the central airways was unaffected. Inflammatory responses to HDM were also reduced in ST2(-/-) mice as reflected by the lower induction of HDM-specific serum IgE, inhibition of HDM-induced eosinophilia and reduced macrophage count in BALF, and a diminished influx of inflammatory cells and reduced goblet cell hyperplasia around the peripheral airways. Furthermore, the levels of the inflammatory cytokines IL-1β, IL-5, IL-13, IL-33, GM-CSF, thymic stromal lymphopoietin and mast cell protease mMCP-1 were reduced in HDM-treated ST2(-/-) mice compared with wild-type controls. In addition to promoting Th2 inflammation, we now suggest a role for the IL-33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease.

Zoltowska AM ，Lei Y ，Fuchs B ，Rask C ，Adner M ，Nilsson GP ... -  《-》

Dietary galacto-oligosaccharides prevent airway eosinophilia and hyperresponsiveness in a murine house dust mite-induced asthma model.

Verheijden KA ，Willemsen LE ，Braber S ，Leusink-Muis T ，Delsing DJ ，Garssen J ，Kraneveld AD ，Folkerts G ... -  《-》

Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma.

Kinker KG ，Gibson AM ，Bass SA ，Day BP ，Deng J ，Medvedovic M ，Figueroa JA ，Hershey GK ，Chen W ... -  《PLoS One》

Allergen-dependent solubilization of IL-13 receptor alpha2 reveals a novel mechanism to regulate allergy.

Daines MO ，Chen W ，Tabata Y ，Walker BA ，Gibson AM ，Masino JA ，Warrier MR ，Daines CL ，Wenzel SE ，Hershey GK ... -  《-》