Akasaki Shoko, Matsushita Kazufumi, Kato Yukinori, Fukuoka Ayumi, Iwasaki Naruhito, Nakahira Masakiyo, Fujieda Shigeharu, Yasuda Koubun, Yoshimoto Tomohiro
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Science, University of Fukui, Fukui 910-1193, Japan.
Int Immunol. 2016 Feb;28(2):65-76. doi: 10.1093/intimm/dxv055. Epub 2015 Oct 1.
Thymic stromal lymphopoietin (TSLP) and IL-33 are epithelium-derived proallergic cytokines that contribute to allergic diseases. Although the involvement of TSLP in allergic rhinitis (AR) is suggested, the exact role of TSLP in AR is poorly understood. Furthermore, the relative contribution of TSLP and IL-33 in nasal allergic responses has not been described. In this study, we examined the roles of TSLP and IL-33 in AR by analyzing acute and chronic AR models. Acute AR mice were intraperitoneally immunized with ragweed, then intranasally challenged with ragweed pollen for four consecutive days. Chronic AR mice were nasally administrated ragweed pollen on consecutive days for 3 weeks. In both models, TSLP receptor (TSLPR)-deficient mice showed defective sneezing responses and reduced serum ragweed-specific IgE levels compared with wild-type (WT) mice. Analyses of bone-marrow chimeric mice demonstrated that hematopoietic cells were responsible for defective sneezing in TSLPR-deficient mice. In addition, FcεRI(+)-cell-specific TSLPR-deficient mice showed partial but significant reduction in sneezing responses. Of note, Th2 activation and nasal eosinophilia were comparable between WT and TSLPR-deficient mice. ST2- and IL-33-deficient mice showed defective Th2 activation and nasal eosinophilia to acute, but not chronic, ragweed exposure. TSLPR and ST2 double-deficient mice showed defective Th2 activation and nasal eosinophilia even after chronic ragweed exposure. These results demonstrate that TSLPR signaling is critical for the early phase response of AR by controlling the IgE-mast-cell/basophil pathway. The IL-33/ST2 pathway is central to nasal Th2 activation during acute allergen exposure, but both TSLPR and ST2 contribute to Th2 responses in chronically allergen-exposed mice.
胸腺基质淋巴细胞生成素（TSLP）和白细胞介素-33（IL-33）是上皮细胞来源的促过敏性细胞因子，与过敏性疾病的发生有关。尽管已有研究提示TSLP参与过敏性鼻炎（AR）的发病过程，但对其在AR中的具体作用仍了解不足。此外，TSLP和IL-33在鼻部过敏反应中的相对作用尚未见报道。在本研究中，我们通过分析急性和慢性AR模型，探讨了TSLP和IL-33在AR中的作用。急性AR小鼠腹腔注射豚草进行免疫，然后连续4天经鼻给予豚草花粉激发。慢性AR小鼠连续3周经鼻给予豚草花粉。在两种模型中，与野生型（WT）小鼠相比，TSLP受体（TSLPR）缺陷小鼠的喷嚏反应减弱，血清豚草特异性IgE水平降低。对骨髓嵌合小鼠的分析表明，造血细胞是导致TSLPR缺陷小鼠喷嚏反应减弱的原因。此外，FcεRI（+）细胞特异性TSLPR缺陷小鼠的喷嚏反应虽有部分但显著降低。值得注意的是，WT小鼠和TSLPR缺陷小鼠之间的Th2细胞活化和鼻黏膜嗜酸性粒细胞增多情况相当。ST2和IL-33缺陷小鼠在急性接触豚草后，Th2细胞活化和鼻黏膜嗜酸性粒细胞增多存在缺陷，但在慢性接触豚草时则无此现象。TSLPR和ST2双缺陷小鼠即使在慢性接触豚草后，Th2细胞活化和鼻黏膜嗜酸性粒细胞增多仍存在缺陷。这些结果表明，TSLPR信号通路通过控制IgE-肥大细胞/嗜碱性粒细胞途径，对AR的早期反应至关重要。IL-33/ST2信号通路在急性过敏原暴露期间对鼻部Th2细胞活化起核心作用，但TSLPR和ST2在慢性过敏原暴露小鼠的Th2细胞反应中均发挥作用。
