Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.
Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.
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DOI：
10.1038/s41385-022-00572-1
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发表时间：
2022-06
影响因子：
8
通讯作者：
Uhlig, Holm H.
中科院分区：
文献类型：
--
作者：
Cavounidis, Athena;Pandey, Sumeet;Capitani, Melania;Friedrich, Matthias;Cross, Amy;Gartner, Lisa;Aschenbrenner, Dominik;Kim-Schulze, Seunghee;Lam, Ying Ka;Berridge, Georgina;McGovern, Dermot P. B.;Kessler, Benedikt;Fischer, Roman;Klenerman, Paul;Hester, Joanna;Issa, Fadi;Torres, Esther A.;Powrie, Fiona;Gochuico, Bernadette R.;Gahl, William A.;Cohen, Louis;Uhlig, Holm H.
Hermansky-Pudlak综合征(HPS)1型和4型是由囊泡运输缺陷引起的。这些患者的克罗恩病样炎症、肺纤维化和巨噬细胞脂质堆积的机制仍然是个谜。本研究的目的是了解HPS-1炎症的细胞基础。我们进行了质量细胞学、蛋白质组学和转录组分析，以研究HPS-1患者的外周血细胞和血清。利用空间转录学，解剖了一例HPS-1肉芽肿性结肠炎患者组织中的肉芽肿相关特征。体外研究了HPS-1患者巨噬细胞和细胞系的抗微生物反应。HPS-1患者的单核细胞表现为炎症表型，与血清中的肿瘤坏死因子、IL-1α、OSM和单核细胞来源的巨噬细胞的异常调节有关。炎性巨噬细胞聚集在肠道中，而HPS-1中的肉芽肿相关巨噬细胞表现出转录特征，提示脂质储存和代谢缺陷。我们发现，HPS1缺乏导致代谢程序的改变和Rab32依赖的放大的mTOR信号，这是通过mTOR在溶酶体上的积累而促进的。这种致病机制转化为异常的细菌清除，可以通过抑制mTORC1来挽救。Rab32介导的mTOR信号作为免疫代谢检查点，增加了有缺陷的生物能量学可以驱动受阻的抗微生物活性并导致炎症的证据。
Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn’s disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.
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DOI：
10.1083/jcb.201605090
发表时间：
2016-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dennis MK;Delevoye C;Acosta-Ruiz A;Hurbain I;Romao M;Hesketh GG;Goff PS;Sviderskaya EV;Bennett DC;Luzio JP;Galli T;Owen DJ;Raposo G;Marks MS
通讯作者：
Marks MS
影响因子：
5.7
作者：
Balci A;Solano-Collado V;Baldassarre M;Spanò S
通讯作者：
Spanò S
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
DOI：
10.1126/science.aag1417
发表时间：
2017-03-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Castellano BM;Thelen AM;Moldavski O;Feltes M;van der Welle RE;Mydock-McGrane L;Jiang X;van Eijkeren RJ;Davis OB;Louie SM;Perera RM;Covey DF;Nomura DK;Ory DS;Zoncu R
通讯作者：
Zoncu R
影响因子：
3.4
作者：
Guo M;Härtlova A;Dill BD;Prescott AR;Gierliński M;Trost M
通讯作者：
Trost M