Generation of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAM.
Generation of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAM.
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DOI：
10.1038/s41419-022-04809-6
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发表时间：
2022-04-13
影响因子：
9
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Lin R;Yi Z;Wang J;Geng S;Li L
中性粒细胞是循环中的主要白细胞，是感染和炎症迹象的第一反应者。虽然中性粒细胞在推动炎症中的作用已经被广泛认识，但中性粒细胞在促进炎症消退中的贡献还没有得到充分的研究。在这里，通过单细胞RNA测序分析，我们鉴定了一组中性粒细胞亚群，表现出促进分解的特征，在静息状态下CD200R和CD86表达更高。我们进一步发现，过氧体应激减压剂4-PBA能有效地培养中性粒细胞进入分解状态，增强CD200R、CD86以及可溶性促分解介质Resolvin D1和serpinB1的表达。4-PBA培养的中性粒细胞吞噬功能增强，杀菌功能增强。从机制上讲，TLR4受体分子TRAM调控的PPARγ/Lmo 4/STAT3信号通路参与了中性粒细胞的产生。我们进一步证明，TRAM的基因缺失导致了分解中性粒细胞的结构性扩张，并伴随着PPARγ/LMO4/STAT3信号通路的增强。这些发现可能对有效训练在治疗急性感染和慢性炎症性疾病中具有治疗潜力的中性粒细胞具有深远的意义。
Neutrophils are the dominant leukocytes in circulation and the first responders to infection and inflammatory cues. While the roles of neutrophils in driving inflammation have been widely recognized, the contribution of neutrophils in facilitating inflammation resolution is under-studied. Here, through single-cell RNA sequencing analysis, we identified a subpopulation of neutrophils exhibiting pro-resolving characteristics with greater Cd200r and Cd86 expression at the resting state. We further discovered that 4-PBA, a peroxisomal stress-reducing agent, can potently train neutrophils into the resolving state with enhanced expression of CD200R, CD86, as well as soluble pro-resolving mediators Resolvin D1 and SerpinB1. Resolving neutrophils trained by 4-PBA manifest enhanced phagocytosis and bacterial-killing functions. Mechanistically, the generation of resolving neutrophils is mediated by the PPARγ/LMO4/STAT3 signaling circuit modulated by TLR4 adaptor molecule TRAM. We further demonstrated that genetic deletion of TRAM renders the constitutive expansion of resolving neutrophils, with an enhanced signaling circuitry of PPARγ/LMO4/STAT3. These findings may have profound implications for the effective training of resolving neutrophils with therapeutic potential in the treatment of both acute infection as well as chronic inflammatory diseases.
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影响因子：
12.3
作者：
Aschenbrenner AC;Mouktaroudi M;Krämer B;Oestreich M;Antonakos N;Nuesch-Germano M;Gkizeli K;Bonaguro L;Reusch N;Baßler K;Saridaki M;Knoll R;Pecht T;Kapellos TS;Doulou S;Kröger C;Herbert M;Holsten L;Horne A;Gemünd ID;Rovina N;Agrawal S;Dahm K;van Uelft M;Drews A;Lenkeit L;Bruse N;Gerretsen J;Gierlich J;Becker M;Händler K;Kraut M;Theis H;Mengiste S;De Domenico E;Schulte-Schrepping J;Seep L;Raabe J;Hoffmeister C;ToVinh M;Keitel V;Rieke G;Talevi V;Skowasch D;Aziz NA;Pickkers P;van de Veerdonk FL;Netea MG;Schultze JL;Kox M;Breteler MMB;Nattermann J;Koutsoukou A;Giamarellos-Bourboulis EJ;Ulas T;German COVID-19 Omics Initiative (DeCOI)
通讯作者：
German COVID-19 Omics Initiative (DeCOI)
影响因子：
5.1
作者：
Batshaw, ML;MacArthur, RB;Tuchman, M
通讯作者：
Tuchman, M
影响因子：
4.6
作者：
Ferracini M;Rios FJ;Pecenin M;Jancar S
通讯作者：
Jancar S
影响因子：
4.4
作者：
Bourke, E;Cassetti, A;Mantovani, A
通讯作者：
Mantovani, A
影响因子：
3.7
作者：
Ericson, Jeffrey A.;Duffau, Pierre;Monach, Paul A.
通讯作者：
Monach, Paul A.