Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging.
Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging.
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DOI：
10.1073/pnas.2015368117
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发表时间：
2020-12-29
影响因子：
11.1
通讯作者：
Leong JM
中科院分区：
文献类型：
--
作者：
Inomata M;Xu S;Chandra P;Meydani SN;Takemura G;Philips JA;Leong JM
老年人表现出对许多传染性病原体的易感性，包括沙门氏菌。肺炎。对S.肺炎与严重疾病相关。S.肺炎克雷伯氏菌在非专职吞噬细胞中触发典型的自噬，但其在巨噬细胞中的作用在很大程度上未被探索。我们发现，BMDM利用自噬，而不是典型的自噬，既消除S。肺炎和调节炎症。值得注意的是，与年轻的BMDM相比，老年的BMDM缺乏抗菌素，导致细菌杀伤受损和促炎反应增强。因此，S.肺炎引发BMDM中的细菌感染，这是一个控制微生物数量和组织损伤性炎症的过程。重要的是，随着年龄的增长，糖尿病的发病率会降低，这可能有助于观察到的老年人对许多传染病的易感性。肺炎链球菌是肺炎和侵袭性疾病的主要原因，特别是在老年人中。S.老年小鼠的肺炎性肺部感染与高细菌负荷和有害的炎症反应有关。巨噬细胞可以通过两种不同的溶酶体运输途径清除微生物并调节炎症，这两种途径涉及1A/1B-轻链3（LC 3）标记的细胞器、典型自噬和LC 3相关的吞噬作用。色葡萄肺炎链球菌成孔毒素肺炎球菌溶血素（pneumolysin，pneumolysin）在非吞噬细胞中触发自噬反应，但pneumolysin在巨噬细胞防御S.肺炎或与年龄相关的感染易感性尚未探索。我们发现，小鼠骨髓来源的巨噬细胞（BMDM）感染的PLY产生的S。pneumoniae触发了LC 3对S的Atg 5和Atg 7依赖性募集。含有肺炎的囊泡。LC 3与S.含有肺炎球菌的吞噬体需要对细菌特异性的组分，如Rubicon和NADPH氧化酶，但不需要典型自噬特异性所需的因子，如Ulk 1、FIP 200或Atg 14。此外，S.肺炎杆菌被隔离在单膜隔室内，表明肺炎杆菌感染。重要的是，与来自年轻（2月龄）小鼠的BMDM相比，来自感染S. pneumoniae不仅缺乏抗菌和杀菌能力，而且产生更高水平的促炎细胞因子。抑制S.来自年轻而非老年小鼠的BMDM中的肺炎链球菌存活和细胞因子应答。因此，BMDM是BMDM控制S的重要先天免疫防御。肺炎感染和伴随的炎症，随着年龄的增长而减少，并可能有助于与年龄相关的易感性，这一重要的病原体。
The elderly exhibit susceptibility to many infectious agents, including S. pneumoniae. A robust acute inflammatory response to S. pneumoniae is associated with severe disease. S. pneumoniae triggers canonical autophagy in nonprofessional phagocytes, but its role in macrophages is largely unexplored. We found that BMDMs utilize LAP, rather than canonical autophagy, to both eliminate S. pneumoniae and modulate inflammation. Notably, compared to young BMDMs, aged BMDMs were deficient in LAP, resulting in compromised bacterial killing and enhanced proinflammatory responses. Thus, S. pneumoniae triggers LAP in BMDMs, a process that controls both microbial numbers and tissue-damaging inflammation. Importantly, LAP diminishes with age and may contribute to the observed susceptibility of the elderly to many infectious diseases. Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.
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DOI：
10.1126/science.1227026
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choy A;Dancourt J;Mugo B;O'Connor TJ;Isberg RR;Melia TJ;Roy CR
通讯作者：
Roy CR
DOI：
10.1083/jcb.201304188
发表时间：
2013-10-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fujita N;Morita E;Itoh T;Tanaka A;Nakaoka M;Osada Y;Umemoto T;Saitoh T;Nakatogawa H;Kobayashi S;Haraguchi T;Guan JL;Iwai K;Tokunaga F;Saito K;Ishibashi K;Akira S;Fukuda M;Noda T;Yoshimori T
通讯作者：
Yoshimori T
影响因子：
5.7
作者：
Bou Ghanem EN;Lee JN;Joma BH;Meydani SN;Leong JM;Panda A
通讯作者：
Panda A
影响因子：
9.6
作者：
Dockrell, David H.;Whyte, Moira K. B.;Mitchell, Timothy J.
通讯作者：
Mitchell, Timothy J.
影响因子：
6.4
作者：
Bewley MA;Naughton M;Preston J;Mitchell A;Holmes A;Marriott HM;Read RC;Mitchell TJ;Whyte MK;Dockrell DH
通讯作者：
Dockrell DH