STAT6 Expression in Multiple Cell Types Mediates the Cooperative Development of Allergic Airway Disease

Abstract

Th2 cells induce asthma through the secretion of cytokines. Two such cytokines, IL-4 and IL-13, are critical mediators of many features of this disease. They both share a common receptor subunit, IL-4Rα, and signal through the STAT6 pathway. STAT6−/− mice have impaired Th2 differentiation and reduced airway response to allergen. Transferred Th2 cells were not able to elicit eosinophilia in response to OVA in STAT6−/− mice. To clarify the role of STAT6 in allergic airway inflammation, we generated mouse bone marrow (BM) chimeras. We observed little to no eosinophilia in OVA-treated STAT6−/− mice even when STAT6+/+ BM or Th2 cells were provided. However, when Th2 cells were transferred to STAT6×Rag2−/− mice, we observed an eosinophilic response to OVA. Nevertheless, the expression of STAT6 on either BM-derived cells or lung resident cells enhanced the severity of OVA-induced eosinophilia. Moreover, when both the BM donor and recipient lacked lymphocytes, transferred Th2 cells were sufficient to induce the level of eosinophilia comparable with that of wild-type (WT) mice. The expression of STAT6 in BM-derived cells was more critical for the enhanced eosinophilic response. Furthermore, we found a significantly higher number of CD4+CD25+ Foxp3+ T cells (regulatory T cells [Tregs]) in PBS- and OVA-treated STAT6−/− mouse lungs compared with that in WT animals suggesting that STAT6 limits both naturally occurring and Ag-induced Tregs. Tregs obtained from either WT or STAT6−/− mice were equally efficient in suppressing CD4+ T cell proliferation in vitro. Taken together, our studies demonstrate multiple STAT6-dependent and -independent features of allergic inflammation, which may impact treatments targeting STAT6.

The Type I and Type II Receptor Complexes for IL-4 and IL-13 Differentially Regulate Allergic Lung Inflammation

“…Our recent findings are in support of this antagonistic relationship between STAT6 and Tregs and IL-4-induced, STAT6-dependent inhibition of FoxP3. We have found that STAT6 -/-mice have higher numbers of Tregs than wildtype mice (Chapoval, et al, 2011). This observation has also been confirmed by Takaki and colleagues who identified a STAT6-binding site in the silencer region in the FoxP3 mRNA transcript.…”

Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner

“…STAT6xRAG2 -/- mice were generated by crossing STAT6 -/- mice and RAG2 -/- mice [18]. The IL-4RαxRAG2 -/- mice were bred at Taconic under contract and then maintained at UMB.…”

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

“…STAT6 knockout mice have no response to IL-4, do not develop Th2 cells in response to IL-4, and fail to produce IgE, bronchial hyperresponsiveness, or BAL eosinophilia and Treg induction after allergen sensitization indicating the critical role of STAT6 in allergic responses (Chapoval et al, 2011;Tomkinson et al, 1999). However there are mechanisms of eosinophil mobilization from the bone marrow that are STAT6-independent .…”