Abstract
The TH2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates TH2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling TH2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γc) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4+ OT-II T cells were adoptively transferred into RAG2−/− and γc −/− mice and allergic lung disease was induced. Both γc −/− and γcxRAG2−/− mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2−/− mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γc −/− mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher TH2 cytokine levels in the BAL and an altered DC phenotype in the γc −/− recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γc-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of TH2 effectors. However, the Type I R regulates AAM protein expression in macrophages.
Highlights
IL-4 and IL-13 are central mediators of asthmatic responses
Since T cells play a critical role in initiating and propagating asthma and cc2/2 mice lack T-cells, we used an asthma model wherein we provided in vivo-primed OVA-specific OT-II T cells to cc– sufficient RAG22/2, cc2/2, or ccxRAG22/2 mice using a previously established transfer model [13]
We have previously found that bone marrow-derived macrophages (BMM) isolated from WT mice induced robust induction of FIZZ1 and YM1 transcripts when stimulated with IL-4 in vitro [12]
Summary
IL-4 and IL-13 are central mediators of asthmatic responses. They initiate and propagate hallmark features of asthma such as pulmonary inflammation, eosinophilia, mucus hypersecretion and airway hyperreactivity by engaging shared receptor complexes and signaling proteins [1,2,3,4]. IL-4 alone, binds to the Type I receptor (R), composed of the IL-4Ra chain and IL-2Rc (common gamma (cc)) chain (reviewed in [5]). IL-4 is critical for TH2 cell differentiation and IgE synthesis, while IL-13 is predominantly responsible for inducing airway hyperesponsiveness and mucus secretion. The reason for this separation of duties is not well understood; relative abundance and differential usage of receptor complexes and signaling pathways in different cell types, together with greater quantities of IL-13 (than IL-4) produced during TH2 responses have been proposed to explain these observations (reviewed in [8]). A recent publication suggested that there may be distinct cellular expression and localization of IL-4 and IL-13 [9]
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