Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice.
Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice.
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DOI：
10.1016/j.jaci.2012.03.002
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Wright JR
中科院分区：
文献类型：
--
作者：
Hsia BJ;Ledford JG;Potts-Kant EN;Nikam VS;Lugogo NL;Foster WM;Kraft M;Abraham SN;Wright JR
肺炎支原体（Mp）经常定植于慢性哮喘患者的气道，并可能导致哮喘恶化。我们先前报道了缺乏表面活性蛋白A（SP-A）的小鼠在肺炎支原体感染期间比TNF-α介导的野生型小鼠气道高反应性（AHR）增加。肥大细胞（MC）参与哮喘模型中的AHR，并产生和应答TNF-α。确定MC/TNF相互作用对MP感染期间缺乏功能性SP-A的气道中AHR的贡献。方法：收集健康人和哮喘患者的支气管肺泡灌洗液，检测TNF-α水平和肺炎支原体（M pneumoniae）阳性率。为了确定SP-A与MCs的相互作用如何调节气道内稳态，我们产生了缺乏SP-A和MCs的小鼠（SP-A−/−KitW-sh/W-sh），并用肺炎支原体感染它们。我们的研究结果表明，高TNF-α水平与人类哮喘患者中肺炎支原体阳性相关，并且人SP-A抑制肺炎支原体刺激的MC转录和释放TNF-α，暗示SP-A的保护作用。肺炎支原体感染的肺中MC数量增加，当MC不存在时，气道反应性显著减弱。使用移植了TNF-α−/−或TNF受体（TNF-R）−/− MCs的SP-A−/−KitW-sh/W-sh小鼠，我们发现，当SP-A缺失时，TNF-α通过TNF-R而不是MC衍生的TNF-α激活MCs，导致肺炎支原体感染期间AHR增加。此外，与移植野生型MC的小鼠相比，移植TNF-α−/−或TNF-R−/− MC的肺炎支原体感染的SP-A−/−KitW-sh/W-sh小鼠的粘液产生减少，而负荷不受影响。我们的数据强调了MC在宿主对病原体感染的反应中作为TNF-α的次级应答者的一个以前未被认识但至关重要的作用。
Mycoplasma pneumoniae (Mp) frequently colonizes the airways of patients with chronic asthma and likely contributes to asthma exacerbations. We previously reported that mice lacking surfactant protein A (SP-A) have increased airway hyperresponsiveness (AHR) during M pneumoniae infection versus wild-type mice mediated by TNF-α. Mast cells (MCs) have been implicated in AHR in asthma models and produce and respond to TNF-α. Determine the contribution of MC/TNF interactions to AHR in airways lacking functional SP-A during Mp infection. Methods: Bronchoalveolar lavage fluid was collected from healthy and asthmatic subjects to examine TNF-α levels and M pneumoniae positivity. To determine how SP-A interactions with MCs regulate airway homeostasis, we generated mice lacking both SP-A and MCs (SP-A−/−KitW-sh/W-sh) and infected them with M pneumoniae. Our findings indicate that high TNF-α levels correlate with M pneumoniae positivity in human asthmatic patients and that human SP-A inhibits M pneumoniae–stimulated transcription and release of TNF-α by MCs, implicating a protective role for SP-A. MC numbers increase in M pneumoniae–infected lungs, and airway reactivity is dramatically attenuated when MCs are absent. Using SP-A−/−KitW-sh/W-sh mice engrafted with TNF-α−/− or TNF receptor (TNF-R)−/− MCs, we found that TNF-α activation of MCs through the TNF-R, but not MC-derived TNF-α, leads to augmented AHR during M pneumoniae infection when SP-A is absent. Additionally, M pneumoniae– infected SP-A−/−KitW-sh/W-sh mice engrafted with TNF-α−/− or TNF-R−/− MCs have decreased mucus production compared with that seen in mice engrafted with wild-type MCs, whereas burden was unaffected. Our data highlight a previously unappreciated but vital role for MCs as secondary responders to TNF-α during the host response to pathogen infection.
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作者：
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DOI：
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发表时间：
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