Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells.
Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells.
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DOI：
10.3389/fimmu.2022.900022
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
表面活性蛋白-A（SP-A）是一种先天性免疫调节剂，调节多种肺部宿主防御功能。我们已经证明SP-A在哮喘中功能失调，这可能部分是由于遗传异质性。在小鼠模型和哮喘参与者的原代支气管上皮细胞中，我们评估了SP-A2特定单核苷酸多态性的功能意义，该多态性导致碳水化合物识别结构域（CRD）内223位氨基酸从谷氨酰胺（Q）取代为赖氨酸（K）。我们发现，与SP-A-2 223 K小鼠相比，SP-A 223 Q人源化小鼠在IL-13暴露后对炎症和粘蛋白产生具有更大的保护。同样地，与具有两个拷贝的次要SP-A 223 K等位基因的哮喘参与者相比，具有两个拷贝的主要223 Q等位基因的哮喘参与者表现出更好的肺功能和哮喘控制。在哮喘参与者的原代支气管上皮细胞中，全长重组SP-A 223 Q比SP-A 223 K更有效地降低IL-13诱导的MUC 5AC基因表达。鉴于这种活性，我们开发了跨越位置223 Q的SP-A2的10和20个氨基酸肽。我们表明，SP-A 223 Q肽减少了屋尘螨哮喘模型中的嗜酸性粒细胞炎症、粘蛋白产生和气道高反应性，保护了小鼠在IL-13激发模型期间的肺功能下降，并降低了哮喘参与者的原代气道上皮细胞中IL-13诱导的MUC 5AC基因表达。这些结果表明，SP-A2的CRD内的位置223可以调节与哮喘相关的几种结果，并且SP-A2的短肽保留了与内源性蛋白类似的抗炎特性。
Surfactant Protein-A (SP-A) is an innate immune modulator that regulates a variety of pulmonary host defense functions. We have shown that SP-A is dysfunctional in asthma, which could be partly due to genetic heterogeneity. In mouse models and primary bronchial epithelial cells from asthmatic participants, we evaluated the functional significance of a particular single nucleotide polymorphism of SP-A2, which results in an amino acid substitution at position 223 from glutamine (Q) to lysine (K) within the carbohydrate recognition domain (CRD). We found that SP-A 223Q humanized mice had greater protection from inflammation and mucin production after IL-13 exposure as compared to SP-A-2 223K mice. Likewise, asthmatic participants with two copies the major 223Q allele demonstrated better lung function and asthma control as compared to asthmatic participants with two copies of the minor SP-A 223K allele. In primary bronchial epithelial cells from asthmatic participants, full-length recombinant SP-A 223Q was more effective at reducing IL-13-induced MUC5AC gene expression compared to SP-A 223K. Given this activity, we developed 10 and 20 amino acid peptides of SP-A2 spanning position 223Q. We show that the SP-A 223Q peptides reduce eosinophilic inflammation, mucin production and airways hyperresponsiveness in a house dust mite model of asthma, protect from lung function decline during an IL-13 challenge model in mice, and decrease IL-13-induced MUC5AC gene expression in primary airway epithelial cells from asthmatic participants. These results suggest that position 223 within the CRD of SP-A2 may modulate several outcomes relevant to asthma, and that short peptides of SP-A2 retain anti-inflammatory properties similar to that of the endogenous protein.
DOI：
10.4049/jimmunol.1500104
发表时间：
2015-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ledford JG;Voelker DR;Addison KJ;Wang Y;Nikam VS;Degan S;Kandasamy P;Tanyaratsrisakul S;Fischer BM;Kraft M;Hollingsworth JW
通讯作者：
Hollingsworth JW
影响因子：
4.4
作者：
Foster, Matthew W.;Thompson, J. Will;Ledford, Julie G.;Dubois, Laura G.;Hollingsworth, John W.;Francisco, Dave;Tanyaratsrisakul, Sasipa;Voelker, Dennis R.;Kraft, Monica;Moseley, M. Arthur;Foster, W. Michael
通讯作者：
Foster, W. Michael