Destructive fibrotic teamwork: how both microenvironment stiffness and profibrotic interleukin 13 impair alveolar macrophage phenotype and function.
Destructive fibrotic teamwork: how both microenvironment stiffness and profibrotic interleukin 13 impair alveolar macrophage phenotype and function.
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破坏性纤维化团队合作：微环境刚度和纤维化白介素如何损害肺泡巨噬细胞表型和功能。
DOI：
10.1039/d2bm00828a
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发表时间：
2022-09-27
影响因子：
6.6
通讯作者：
Fromen, Catherine A.
中科院分区：
文献类型：
--
作者：
Bomb, Kartik;Pradhan, Lina;Zhang, Qi;Jarai, Bader M.;Bhattacharjee, Arnab;Burris, David L.;Kloxin, April M.;Fromen, Catherine A.
肺纤维化微环境的特征在于肺组织的硬度增加和促纤维化可溶性因子的分泌增强，其有助于导致失调的伤口愈合和肺衰竭的反馈回路。精确定位促纤维化刺激在损害免疫细胞应答中的个体和串联效应仍然很困难，并且需要改进治疗策略。我们利用统计实验设计（DOE）来研究微环境硬度和白细胞介素13（IL 13），一种与疾病严重程度相关的促纤维化可溶性因子，如何促进肺纤维化中常见的受损巨噬细胞反应。我们使用了不同硬度的工程生物启发水凝胶，从健康到纤维化肺组织，以及培养的小鼠肺泡巨噬细胞（MH-S细胞），有或没有IL 13，以量化细胞反应并分析其独立和协同作用。我们发现，虽然硬度和IL 13都独立地影响巨噬细胞的形态、表型、吞噬作用和巨噬细胞吞噬作用，但这些因素协同作用以加剧受损的巨噬细胞表型和巨噬细胞吞噬作用。这些由创新方法实现的独特发现提供了对纤维化条件下巨噬细胞如何在清除碎片方面不那么有效的见解，有助于纤维化的开始/进展，并更广泛地告知纤维化的潜在驱动因素如何调节免疫细胞反应以告知治疗策略。巨噬细胞的交替活化（M2表型）和减少的吞噬作用通过增加的底物硬度和促纤维化可溶性线索的存在协同调节。
The pulmonary fibrotic microenvironment is characterized by increased stiffness of lung tissue and enhanced secretion of profibrotic soluble cues contributing to a feedback loop that leads to dysregulated wound healing and lung failure. Pinpointing the individual and tandem effects of profibrotic stimuli in impairing immune cell response remains difficult and is needed for improved therapeutic strategies. We utilized a statistical design of experiment (DOE) to investigate how microenvironment stiffness and Interleukin 13 (IL13), a profibrotic soluble factor linked with disease severity, contribute to the impaired macrophage response commonly observed in pulmonary fibrosis. We used engineered bioinspired hydrogels of different stiffness, ranging from healthy to fibrotic lung tissue, and cultured murine alveolar macrophages (MH-S cells) with or without IL13 to quantify cell response and analyze their independent and synergistic effects. We found that, while both stiffness and IL13 independently influence macrophage morphology, phenotype, phagocytosis and efferocytosis, these factors work synergistically to exacerbate impaired macrophage phenotype and efferocytosis. These unique findings enabled by the innovative approach provide insights into how macrophages in fibrotic conditions are not as effective in clearing debris, contributing to fibrosis initiation/progression, and more broadly inform how underlying drivers of fibrosis modulate immune cell response to inform therapeutic strategies. Alternative activation (M2 phenotype) of macrophages and reduced phagocytosis is regulated synergistically by increased substrate stiffness and presence of profibrotic soluble cues.
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影响因子：
--
作者：
Fereol, Sophie;Fodil, Redouane;Planus, Emmanuelle
通讯作者：
Planus, Emmanuelle
影响因子：
2.9
作者：
Ekström M;Gustafson T;Boman K;Nilsson K;Tornling G;Murgia N;Torén K
通讯作者：
Torén K
DOI：
10.4049/jimmunol.1601520
发表时间：
2017-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elliott MR;Koster KM;Murphy PS
通讯作者：
Murphy PS
DOI：
10.1152/ajplung.00043.2011
发表时间：
2011-09-01
影响因子：
4.9
作者：
Desai, Leena P.;Wu, Yidi;Gunst, Susan J.
通讯作者：
Gunst, Susan J.
DOI：
10.1164/rccm.201809-1775oc
发表时间：
2019-07-15
影响因子：
24.7
作者：
Allden, Sarah J.;Ogger, Patricia P.;Byrne, Adam J.
通讯作者：
Byrne, Adam J.