CD300f associates with IL-4 receptor α and amplifies IL-4-induced immune cell responses
CD300f associates with IL-4 receptor α and amplifies IL-4-induced immune cell responses
复制标题
DOI：
10.1073/pnas.1507625112
复制
发表时间：
2015-07-14
影响因子：
11.1
通讯作者：
Munitz, Ariel
中科院分区：
文献类型：
--
作者：
Moshkovits, Itay;Karo-Atar, Danielle;Munitz, Ariel
IL-4受体（R）α是IL-4和IL-13的共同受体链，是IL-4和IL-13介导的信号传导和随后效应子功能（如在2型炎症反应中观察到的那些）的关键组分。尽管如此，是否存在能够放大IL-4 R α诱导反应的内在途径仍然未知。在这项研究中，我们确定了骨髓相关的IG受体CD 300 f作为IL-4诱导的巨噬细胞中的分子。随后的分析表明，CD 300 f与IL-4 R α共定位并物理相关。使用Cd 300 f（-/-）细胞和受体交联实验，我们确定CD 300 f通过增强IL-4/IL-13诱导的信号传导、介质释放和引发来放大IL-4 R α诱导的应答。一致地，IL-4和空气变应原处理的Cd 300 f（-/-）小鼠显示IgE产生、趋化因子表达和炎性细胞募集减少。Cd 300 f（-/-）小鼠中的应答受损不是由于不能产生适当的Th 2应答，因为在变应原激发的Cd 300 f（-/-）小鼠中IL-4/IL-13水平显著增加，这一发现与细胞因子消耗减少一致。最后，从变应性鼻炎患者中获得的单核细胞和嗜酸性粒细胞中CD 300 f表达增加。总的来说，我们的数据突出了CD 300 f在IL-4 R α诱导的免疫细胞应答中先前未鉴定的作用。这些数据为IL-4 R α诱导反应的分子机制提供了新的见解，并可能为过敏和哮喘中靶向IL-4提供新的治疗工具。
IL-4 receptor (R) alpha, 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 alpha-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 alpha. Using Cd300f(-/-) cells and receptor cross-linking experiments, we established that CD300f amplified IL-4R alpha-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 alpha-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4R alpha-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.