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

Abstract

BackgroundCD4+ T helper type 2 (TH2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also drive alternative activation of macrophages (AAM). However, the precise roles played by the IL-4/IL-13 receptors and STAT6 in inducing AAM protein expression and modulating specific features of airway inflammation are still unclear. Since TH2 differentiation and activation plays a pivotal role in this disease, we explored the possibility of developing an asthma model in mice using T cells that were differentiated in vivo.ResultsIn this study, we monitored the activation and proliferation status of adoptively transferred allergen-specific naïve or in vivo primed CD4+ T cells. We found that both the naïve and in vivo primed T cells expressed similar levels of CD44 and IL-4. However, in vivo primed T cells underwent reduced proliferation in a lymphopenic environment when compared to naïve T cells. We then used these in vivo generated effector T cells in an asthma model. Although there was reduced inflammation in mice lacking IL-4Rα or STAT6, significant amounts of eosinophils were still present in the BAL and lung tissue. Moreover, specific AAM proteins YM1 and FIZZ1 were expressed by epithelial cells, while macrophages expressed only YM1 in RAG2-/- mice. We further show that FIZZ1 and YM1 protein expression in the lung was completely dependent on signaling through the IL-4Rα and STAT6. Consistent with the enhanced inflammation and AAM protein expression, there was a significant increase in collagen deposition and smooth muscle thickening in RAG2-/- mice compared to mice deficient in IL-4Rα or STAT6.ConclusionsThese results establish that transfer of in vivo primed CD4+ T cells can induce allergic lung inflammation. Furthermore, while IL-4/IL-13 signaling through IL-4Rα and STAT6 is essential for AAM protein expression, lung inflammation and eosinophilia are only partially dependent on this pathway. Further studies are required to identify other proteins and signaling pathways involved in airway inflammation.

Resistin-Like Molecule α Stimulates Proliferation of Mesenchymal Stem Cells While Maintaining Their Multipotency

“…RELMa is expressed by macrophages and pulmonary epithelial cells [2] and also by pulmonary vascular cells during hypoxia [1]. The Th-2 cytokines IL-4 and IL-13 induce RELMa expression via STAT6 and JAK-1 pathways [3,5]. RELMa has the capacity to promote lung cell proliferation, angiogenesis, and inflammation [1,6].…”

Contribution of Alternatively Activated Macrophages to Allergic Lung Inflammation: A Tale of Mice and Men

“…Loss of STAT6 signaling caused a significant reduction in Retnla and Chi3L3 mRNA levels in bleomycin-induced lung fibrosis and allergic peritonitis models, respectively [27,28]. Using a murine model of asthma, we found that the number of AAMs recruited to the lungs in mice lacking STAT6 or IL-4Rα was much lower when compared to wild-type (WT) mice [29]. It has also been demonstrated that promoter regions of the Arg1 , Retnla and Chi3L3 genes have consensus STAT6-binding sites [28,30,31].…”

“…The contribution of FIZZ1 to asthma is still unclear. Our studies have shown that IL-4 induces robust induction of FIZZ1 mRNA in macrophages in vitro [25], but FIZZ1 protein expression in these cells was absent in vivo in a mouse model of asthma [29]. …”

“…FIZZ1 was originally discovered in bronchoalveolar lavage fluid in a mouse model of asthma [77]. Elevated levels of FIZZ1 mRNA have since been detected in parasite infection models [69], allergic lung inflammation [28,29,77], allergic peritonitis [28], bleomycin-induced lung fibrosis [27] and hypoxia-induced pulmonary hypertension [78]. FIZZ1 has been reported to induce smooth muscle proliferation and actin and collagen deposition, causing fibrosis [79].…”

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

“…Previous work has shown that B cells from mice lacking STAT6 failed to produce significant amounts of IgE and IgG1 after infection with the nematode parasites (Raia et al, 2011;Turqueti-Neves et al, 2014). The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters. Recently, IL-4-driven STAT6 constitutive activation has been found in various diseases, such as allergy (Hong et al, 2014), tumors (Cheah et al, 2014;Creytens et al, in press;Koelsche et al, 2014), and lymphoproliferative disorders (Rawal et al, 2013).…”