期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8708-8713
DOI：10.1073/pnas.1507625112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIL-4 receptor (R) is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in allergy. Thus, it is a primary therapeutic target in diseases such as atopic dermatitis and asthma. Despite extensive studies, it is unknown whether an additional receptor system exists that may act to amplify IL-4R signaling and subsequent IL-4/IL-13-induced responses. We now report that CD300f is physically associated with IL-4R and potently amplifies IL-4R-induced responses in vitro and in vivo. Our results establish CD300f as a previously unidentified IL-4R coreceptor. To the best of our knowledge, this is the first report of an additional receptor that serves to amplify the IL-4 signaling pathway. IL-4 receptor (R) , the common receptor chain for IL-4 and IL-13, is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4R-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4R. Using Cd300f-/- cells and receptor cross-linking experiments, we established that CD300f amplified IL-4R-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4- and aeroallergen-treated Cd300f-/- mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f-/- mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f-/- mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4R-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4R-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.
