CC16 drives VLA-2-dependent SPLUNC1 expression.
CC16 drives VLA-2-dependent SPLUNC1 expression.
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CC 16驱动VLA-2依赖性SPLUNC 1表达。
DOI：
10.3389/fimmu.2023.1277582
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
CC16（俱乐部细胞分泌蛋白）是由俱乐部细胞和肺内其他非纤毛上皮细胞产生的蛋白质。CC16已被证明可以预防阻塞性肺疾病的发展和减轻肺部病原体负担。尽管最近在了解CC16在循环中的作用方面取得了进展，但CC16在肺上皮反应中的生物学机制尚未阐明。我们试图确定CC16缺乏是否会损害上皮驱动的宿主反应，并确定在肺上皮内表达的新受体，CC16通过这些受体赋予活性。我们利用质谱法和定量蛋白质组学研究CC16缺乏如何影响顶端分泌的肺上皮蛋白。研究了naïve条件下小鼠气管上皮细胞（MTECS）、人鼻上皮细胞（HNECs）和小鼠。我们鉴定出8种抗菌蛋白被CC16-/- MTECS显著降低，其中6种在严重哮喘研究计划（SARP）队列中通过mRNA表达得到验证。短腭肺和鼻上皮克隆1 （SPLUNC1）是差异表达最多的蛋白（66倍），是本研究的重点。通过MTECs和HNECs的结合，我们发现CC16通过受体复合体Very Late Antigen-2 （VLA-2）的信号传导增强肺上皮驱动的SPLUNC1表达，给予小鼠rCC16增强肺SPLUNC1的产生并减少肺炎支原体（Mp）负担。同样，rSPLUNC1导致缺乏CC16小鼠的Mp负荷降低。rCC16内的vas -2整合素结合位点是诱导SPLUNC1和减少Mp负担所必需的。我们的研究结果表明，CC16通过上调抗菌素在上皮驱动的宿主防御中发挥了新的作用，并为CC16定义了一种新的上皮受体VLA-2，通过该受体信号传导是增强SPLUNC1产生所必需的。
CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated. We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity. We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge. We identified 8 antimicrobial proteins significantly decreased by CC16-/- MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases Mycoplasma pneumoniae (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden. Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production.
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影响因子：
5.8
作者：
Chu HW;Gally F;Thaikoottathil J;Janssen-Heininger YM;Wu Q;Zhang G;Reisdorph N;Case S;Minor M;Smith S;Jiang D;Michels N;Simon G;Martin RJ
通讯作者：
Martin RJ
影响因子：
14.9
作者：
Mashiach E;Nussinov R;Wolfson HJ
通讯作者：
Wolfson HJ
影响因子：
3.7
作者：
Jiang, Di;Wenzel, Sally E.;Chu, Hong Wei
通讯作者：
Chu, Hong Wei
影响因子：
7
作者：
Kruse, Rikke;Krantz, James;Langlais, Paul R.
通讯作者：
Langlais, Paul R.
影响因子：
3.4
作者：
Pang M;Liu HY;Li T;Wang D;Hu XY;Zhang XR;Yu BF;Guo R;Wang HL
通讯作者：
Wang HL