Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses.
Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses.
复制标题
DOI：
10.4049/jimmunol.1500104
复制
发表时间：
2015-06-15
期刊：
影响因子：
--
通讯作者：
Hollingsworth JW
中科院分区：
文献类型：
--
作者：
Ledford JG;Voelker DR;Addison KJ;Wang Y;Nikam VS;Degan S;Kandasamy P;Tanyaratsrisakul S;Fischer BM;Kraft M;Hollingsworth JW
肺炎支原体（Mp）是一种定植于呼吸道粘膜表面的细胞外病原体，与哮喘急性发作相关。以往的研究表明，表面活性蛋白-A（SP-A）与活支原体和支原体膜（MMF）具有高亲和力。人类表达SP-A的单氨基酸遗传变异体，可能与肺部疾病相关，我们的研究结果表明，SP-A2（Gln 223 Lys）的等位基因差异影响与MMF的结合。我们发现SP-A−/−小鼠对MMF暴露更敏感，并且粘蛋白产生和中性粒细胞募集显著增加。与SP-A−/−小鼠相比，携带hSP-A2 223 K等位基因的新型人源化SP-A2转基因小鼠在用MMF攻击时表现出肺中中性粒细胞流入和粘蛋白产生减少。相反，表达hSP-A2 223 Q的小鼠具有增加的中性粒细胞流入和粘蛋白产生，这与SP-A−/−小鼠相似。使用气管上皮细胞培养，我们表明，增强粘蛋白生产的霉酚酸酯发生在SP-A的情况下，并不依赖于中性粒细胞招聘。当SP-A不存在时，在MMF激发的小鼠的肺中表皮生长因子受体（EGFR）的磷酸化增加是明显的。MMF激发前EGFR的药理学抑制显著降低SP-A−/−小鼠的粘蛋白生成。这些发现表明SP-A在限制MMF刺激的粘蛋白产生中的保护作用，这种作用是通过干扰EGFR介导的信号传导发生的。SP-A与EGFR信号通路的相互作用似乎以等位基因特异性方式发生，这可能对人类疾病中的SP-A多态性具有重要意义。
Mycoplasma pneumoniae (Mp) is an extracellular pathogen that colonizes mucosal surfaces of the respiratory tract and is associated with asthma exacerbations. Previous reports demonstrate that surfactant protein-A (SP-A) binds live Mp and mycoplasma membranes (MMF) with high affinity. Humans express a repertoire of single amino acid genetic variants of SP-A that may be associated with lung disease, and our findings demonstrate that allelic differences in SP-A2 (Gln223Lys) affect the binding to MMF. We show that SP-A−/− mice are more susceptible to MMF exposure and have significant increases in mucin production and neutrophil recruitment. Novel humanized-SP-A2 transgenic mice harboring the hSP-A2 223K allele exhibit reduced neutrophil influx and mucin production in the lungs, when challenged with MMF, compared to SP-A−/− mice. Conversely, mice expressing hSP-A2 223Q have increased neutrophil influx and mucin production that is similar to SP-A−/− mice. Using tracheal epithelial cell cultures, we show that enhanced mucin production to MMF occurs in the absence of SP-A, and is not dependent upon neutrophil recruitment. Increased phosphorylation of the epidermal growth factor receptor (EGFR) was evident in the lungs of MMF-challenged mice when SP-A was absent. Pharmacologic inhibition of EGFR prior to MMF challenge dramatically reduced mucin production in SP-A−/− mice. These findings suggest a protective role for SP-A in limiting MMF-stimulated mucin production that occurs through interference with EGFR mediated signaling. The SP-A interaction with the EGFR signaling pathway appears to occur in an allele specific manner that may have important implications for SP-A polymorphisms in human diseases.
登录
查看更多内容
DOI：
10.1165/ajrcmb/6.4.446
发表时间：
1992-04-01
影响因子：
6.4
作者：
KATYAL, SL;SINGH, G;LOCKER, J
通讯作者：
LOCKER, J
影响因子：
3.7
作者：
Ledford JG;Mukherjee S;Kislan MM;Nugent JL;Hollingsworth JW;Wright JR
通讯作者：
Wright JR
影响因子：
5.1
作者：
El Saleeby, Chadi M.;Li, Rongling;DeVincenzo, John P.
通讯作者：
DeVincenzo, John P.
DOI：
10.1165/ajrcmb.20.2.3303
发表时间：
1999-02-01
影响因子：
6.4
作者：
LeVine, AM;Kurak, KE;Korfhagen, TR
通讯作者：
Korfhagen, TR
影响因子：
3.5
作者：
Floros, J;Fan, R;Merrill, J
通讯作者：
Merrill, J