Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

Abstract

Both thymic stromal lymphopoietin (TSLP) and IL-13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL- 13 has not yet been fully elucidated. This study aimed to investigate whether IL-13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL-13 induced TSLP expression in mouse nasal tissue specimens in a Stat6-dependent manner. In addition, intranasal challenge of mice with IL-13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL-13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti-TSLP Ab. These findings suggest that TSLP is an important mediator of IL-13-driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL-13 is a critical downstream element for TSLP-driven allergic inflammation, TSLP may function both upstream and downstream of IL-13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.Key words: Allergic inflammation . Epithelial cells . IL-13 . Thymic stromal lymphopoietin Supporting Information available online IntroductionThymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, which binds to a TSLP receptor (TSLPR) consisting of the IL-7 receptor a-chain and a common g receptor-like chain [1,2]. TSLP was originally identified as a factor derived from a thymic stromal cell line that could support the growth of a mouse B-cell line [3].However, recent evidence has demonstrated TSLP, derived from epithelial cells, to be a critical factor for allergic inflammation [1,2,4]. For instance, transgenic mice expressing TSLP in keratinocytes or in lung epithelial cells develop atopic dermatitisor asthma-like inflammation in the skin or the lung, respectively, while TSLPR-deficient mice fail to develop an inflammatory lung response to inhaled antigen [5][6][7].IL-13, a Th2-type cytokine, is a central mediator for allergic inflammation [8,9]. The blockade of IL-13 markedly inhibits allergen-induced airway hyperresponsiveness, mucus production, and eosinophilia whereas IL-13 delivery to the airway causes SHORT COMMUNICATION 3078these effects in mice [8][9][10][11]. Therefore, IL-13 as well as TSLP is necessary and sufficient for the development of allergic inflammation. However, the relationship between TSLP and IL-13 in allergic inflammation has not yet been fully elucidated.This study thus investigated the causal link between IL-13 and TSLP in allergic inflammation. For this purpose, we examined the effects of IL-13 on TSLP expression both in vitro and in vivo using mouse nasal tissue explants and a mouse model of allergic inflammation in the nasal mucosa, respectively. The current results suggest that TSLP is induced by IL-13 and is critical for the development of IL-13-driven allergic inflammation. Because recent studies suggest that TSLP-dri...

Biology of Lung Dendritic Cells at the Origin of Asthma

“…Therefore, it will be very important to study how the production of TSLP by epithelial cells and other inflammatory cells is regulated. Strikingly, IL-13 was shown to induce expression of TSLP, pointing out to an important feedback-loop acting via DCs to enhance Th2 cell immunity (Miyata et al, 2009).…”

Strategies targeting the IL-4/IL-13 axes in disease

“…Nasal IL-13 installation was found to induce eosinophilia and goblet cell hypertrophy in the nasal mucosa of mice which could be decreased by approximately 60% by pretreatment with systemic TSLP-neutralising mAb [244]. Ex vivo, IL-13 was found to induce TSLP expression in mouse nasal explants in a STAT-6 dependent and mast cell independent fashion [244].…”

“…Ex vivo, IL-13 was found to induce TSLP expression in mouse nasal explants in a STAT-6 dependent and mast cell independent fashion [244]. In a systemic sensitization and nasal challenge model of mouse nasal allergy IL-13 neutralization with soluble IL-13Ra2-Fc reduced nasal blockage (via the surrogate of respiratory rate as mice are obligate nasal breathers) and nasal resistance without affecting eosinophils in nasal tissue [245].…”

The Regulation of Thymic Stromal Lymphopoietin in Gut Immune Homeostasis

“…The positive regulator NF-jB mediates TSLP gene expression in conjunction with IL-1b and TNF-a [28,29], but may alternatively be controlled via the MAPK pathway [30]. TSLP induced by the TLR3 ligand dsRNA or its agonist poly(I:C) is dependent upon NF-jB, interferon regulatory factor 3(IRF3) and activating protein (AP)-1, while IL-4 and IL-13 induce TSLP expression in an STAT6-dependent manner [27,[31][32][33]. The known negative regulator, a heterodimer formed between retinoid X receptors (RXR)a and/or RXRb and free vitamin D receptor (VDR) or the retinoic acid receptor-c, act as co-repressors [34,35].…”