Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice.
Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice.
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黏脂素3缺陷型小鼠的肺气肿及巨噬细胞弹性蛋白酶清除功能受损
DOI：
10.1038/s41467-021-27860-x
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发表时间：
2022-01-14
影响因子：
16.6
通讯作者：
Grimm C
中科院分区：
文献类型：
--
作者：
Spix B;Butz ES;Chen CC;Rosato AS;Tang R;Jeridi A;Kudrina V;Plesch E;Wartenberg P;Arlt E;Briukhovetska D;Ansari M;Günsel GG;Conlon TM;Wyatt A;Wetzel S;Teupser D;Holdt LM;Ectors F;Boekhoff I;Boehm U;García-Añoveros J;Saftig P;Giera M;Kobold S;Schiller HB;Zierler S;Gudermann T;Wahl-Schott C;Bracher F;Yildirim AÖ;Biel M;Grimm C
肺气肿和慢性支气管炎是慢性阻塞性肺疾病的两个最常见的原因。过量的巨噬细胞弹性蛋白酶MMP-12主要由肺泡巨噬细胞分泌，已知其介导肺损伤和肺气肿的发展。在这里，我们发现了内溶酶体阳离子通道粘磷脂3（TRPML 3）作为MMP-12从支气管肺泡液中再摄取的调节剂，在两个独立产生的Trpml 3 −/−小鼠模型中驱动肺损伤扩大，在弹性蛋白酶或烟草烟雾治疗后进一步加剧。从机制上讲，使用Trpml 3 IRES-Cre/eR 26-τGFP报告小鼠模型、转录组学和内溶酶体膜片钳实验，我们表明在肺中TRPML 3几乎仅在肺泡巨噬细胞中表达，其中其损失导致MMP-12的早期内体运输和内吞作用的缺陷。我们的研究结果表明，TRPML 3代表了肺泡巨噬细胞清除MMP-12的关键调节因子，并可能作为肺气肿和慢性阻塞性肺疾病的治疗靶点。过量的巨噬细胞弹性蛋白酶MMP-12是慢性阻塞性肺疾病的主要驱动因素。在这里，作者表明，内溶酶体离子通道TRPML 3是MMP-12的细胞再摄取的调节剂，从而中和肺中有害的MMP-12。
Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3−/− mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
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DOI：
10.1056/nejmoa0904006
发表时间：
2009-12-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hunninghake GM;Cho MH;Tesfaigzi Y;Soto-Quiros ME;Avila L;Lasky-Su J;Stidley C;Melén E;Söderhäll C;Hallberg J;Kull I;Kere J;Svartengren M;Pershagen G;Wickman M;Lange C;Demeo DL;Hersh CP;Klanderman BJ;Raby BA;Sparrow D;Shapiro SD;Silverman EK;Litonjua AA;Weiss ST;Celedón JC
通讯作者：
Celedón JC
DOI：
10.1073/pnas.1920122117
发表时间：
2020-07-28
影响因子：
11.1
作者：
Arlt, Elisabeth;Fraticelli, Marco;Zierler, Susanna
通讯作者：
Zierler, Susanna
影响因子：
8.6
作者：
Chen, Cheng-Chang;Butz, Elisabeth S.;Grimm, Christian
通讯作者：
Grimm, Christian
影响因子：
16.6
作者：
Angelidis, Ilias;Simon, Lukas M.;Schiller, Herbert B.
通讯作者：
Schiller, Herbert B.
影响因子：
24.3
作者：
Ishii, Takeo;Abboud, Raja T.;Sandford, Andrew J.
通讯作者：
Sandford, Andrew J.