Stat6-Deficient Mice Develop Airway Hyperresponsiveness and Peribronchial Fibrosis during Chronic Fungal Asthma

Abstract

Signal transducer and activator of transcription 6 (Stat6) is critical for Th2-mediated responses during allergic airway disease. To investigate the role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling, Stat6-deficient (Stat6-/-) and Stat6-wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and airway disease was subsequently assessed in both groups at days 21, 30, 38, and 44 after an intratracheal challenge with live A. fumigatus conidia. At all times after conidia, histological analysis revealed an absence of goblet cell hyperplasia and markedly diminished peribronchial inflammation in Stat6-/- mice in contrast to Stat6+/+ mice. Airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice were significantly reduced at day 21 after conidia compared with Stat6+/+ mice, but both groups exhibited significant, similar increases in these parameters at all subsequent times after conidia. In separate experiments, IL-13-responsive cells in Stat6-/- mice were targeted via the daily intranasal administration of 200 ng of IL-13-PE38QQR (IL13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, from days 38 to 44 after the conidia challenge. IL13-PE treatment abolished airway hyperresponsiveness, but not peribronchial fibrosis in Stat6-/- mice. Taken together, these data demonstrate that the chronic development of airway hyperresponsiveness during fungal asthma is IL-13-dependent but Stat6-independent.

Interleukin-13 Fusion Cytotoxin Arrests Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice

“…37,38,56,57 The utility of this molecule was also recently described in two independent studies of a model of chronic allergic airway disease induced by A. fumigatus. 31,32 Because IL13-PE targeted IL-4R␣-and IL-13R␣1-positive cells in the allergic lung 31,32 and in the lungs of mice challenged with live S. mansoni eggs (observed in the present study), this chimeric protein provided an effective treatment for attenuating the granulomatous and Th2 responses invoked by S. mansoni eggs. The data shown herein demonstrate that the intranasal administration of IL13-PE, whether given immediately after (according to protocol 1) or at day 8 (according to protocol 2) after S. mansoni egg injection, significantly reduced the S. mansoni egg-induced granuloma formation.…”

“…37,38 We have previously shown that IL13-PE (at a dose of 200 ng/dose) ameliorated chronic fungal asthma in two independent studies. 31,32 The dosing protocols used in the present study are outlined in Figure 1. In the first protocol, groups of 15 mice received a 200 ng/dose of IL13-PE dissolved in 10 l of phosphate-buffered saline (PBS) containing 0.25% human serum albumin, or diluent, via an intranasal bolus starting immediately after and every other day until day 8 after the S. mansoni egg challenge.…”

“…We have previously used IL13-PE to successfully reverse all of the Th2-associated features of Aspergillus fumigatus-induced allergic airway disease including airway hyperreactivity and airway remodeling. 31,32 In addition, IL13-PE markedly reduced or abolished the whole lung expression of IL-4R␣ and IL-13R␣1 during Aspergillus-induced allergic airway disease demonstrating that this IL-13 immunotoxin targets cells that are responsive to IL-4 and IL-13. 31,32 The present study showed that when given immediately after or as late as 8 days after the intravenous injection of live S. mansoni eggs, IL13-PE treatment significantly arrested the development of the Th2-mediated pulmonary granulomatous response.…”

“…31,32 In addition, IL13-PE markedly reduced or abolished the whole lung expression of IL-4R␣ and IL-13R␣1 during Aspergillus-induced allergic airway disease demonstrating that this IL-13 immunotoxin targets cells that are responsive to IL-4 and IL-13. 31,32 The present study showed that when given immediately after or as late as 8 days after the intravenous injection of live S. mansoni eggs, IL13-PE treatment significantly arrested the development of the Th2-mediated pulmonary granulomatous response. Interestingly, the IL13-PE treatment seemed to be mediated through the inhibition of IL-4, IL-13, and a concomitant dramatic increase in IL-13 decoy receptor (ie, IL-13R␣2) expression.…”

IgE Generation and Mast Cell Effector Function in Mice Deficient in IL-4 and IL-13

“…In addition, the finding that IL-15 can trigger STAT6 phosphorylation in mast cells (65) raises the possibility that cytokines other than IL-4 or IL-13 could use STAT6 to drive IgE production. Others have shown that mice lacking STAT6 exhibit various IL-13-mediated allergic-type responses (66) and can even produce IgE under certain activation conditions (23), raising the alternative possibility of a STAT6-independent pathway leading to IgE in mice lacking IL-4 and IL-13. Finally, even though IL-4 and IL-13 may facilitate IgE switch recombination, the event may occur at some low rate even in the absence of these agents.…”