The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.
The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice.
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DOI：
10.4049/jimmunol.1700216
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发表时间：
2017-08-15
期刊：
影响因子：
--
通讯作者：
Hershenson MB
中科院分区：
文献类型：
--
作者：
Han M;Rajput C;Hong JY;Lei J;Hinde JL;Wu Q;Bentley JK;Hershenson MB
早期呼吸道病毒感染是哮喘发生的危险因素。鼻病毒（RV）感染6日龄但未成熟的小鼠引起粘膜化生和气道高反应性，其与肺2型先天淋巴细胞（ILC 2）的扩增相关并依赖于IL-13和先天细胞因子IL-25。然而，其他先天性细胞因子，IL-33和胸腺基质淋巴细胞生成素（TSLP），观察到的哮喘样表型的贡献还没有被检查。我们推断，IL-33和TSLP的表达也诱导RV感染在未成熟的小鼠，并需要最大的ILC 2扩增和粘膜化生。我们用假HeLa细胞裂解物或RV接种六日龄BALB/c（野生型）和TSLP受体敲除（TSLPR KO）小鼠。用IL-33或重组IL-33、IL-25或TSLP的中和抗体处理所选小鼠。从RV感染的未成熟小鼠中分离ILC 2并用先天性细胞因子离体处理。RV感染6日龄小鼠增加IL-33和TSLP蛋白丰度。TSLP表达定位于气道上皮，而IL-33表达于上皮细胞和上皮下细胞。RV诱导的粘膜化生、ILC 2扩增、气道高反应性和上皮细胞IL-25表达通过抗IL-33治疗和在TSLPR KO小鼠中减弱。给予鼻内IL-33，而不是TSLP，足以治疗粘膜化生。最后，TSLP是响应IL-25和IL-33的最大ILC 2基因表达所必需的。在未成熟的RV感染小鼠中产生的粘液化生涉及先天细胞因子IL-25、IL-33和TSLP之间的复杂相互作用。
Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of six-day old but not mature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with expansion of lung type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined. We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and required for maximum ILC2 expansion and mucous metaplasia. We inoculated six day-old BALB/c (wild-type) and TSLP receptor knockout (TSLPR KO) mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing antibodies to IL-33 or recombinant IL-33, IL-25 or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo. RV infection of six-day old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in both epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLPR KO mice. Administration of intranasal IL-33, but not TSLP, was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33. The generation of mucous metaplasia in immature, RV-infected mice involves a complex interplay between the innate cytokines IL-25, IL-33 and TSLP.
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影响因子：
14.2
作者：
Lee, Hai-Chon;Headley, Mark B.;Loo, Yueh-Ming;Berlin, Aaron;Gale, Michael, Jr.;Debley, Jason S.;Lukacs, Nicholas W.;Ziegler, Steven F.
通讯作者：
Ziegler, Steven F.
DOI：
10.1073/pnas.1208092109
发表时间：
2012-10-09
影响因子：
11.1
作者：
Korfhagen, Thomas R.;Kitzmiller, Joseph;Whitsett, Jeffrey A.
通讯作者：
Whitsett, Jeffrey A.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
32.4
作者：
Halim, Timotheus Y. F.;Krauss, Ramona H.;Takei, Fumio
通讯作者：
Takei, Fumio
影响因子：
14.2
作者：
Barlow, Jillian L.;Bellosi, Agustin;McKenzie, Andrew N. J.
通讯作者：
McKenzie, Andrew N. J.