PLC and PAD2 Regulate Extracellular Calcium-Triggered Release of Macrophage Extracellular DNA Traps

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Neha Mishra, Magdalena Mohs, Nico Wittmann, Stefan Gross, Paul R. Thompson, Lukas Bossaller
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Abstract

Macrophages can respond to infection or cellular stress by forming inflammasomes or by releasing extracellular traps (ETs) of DNA through METosis. While ETs have been extensively studied in neutrophils, there are fewer studies on METosis. We show that extracellular calcium and LPS enable human monocyte-derived macrophages (hMDM) to release extracellular DNA decorated with myeloperoxidase (MPO) and citrullinated histone, alongside ASC aggregation and IL-1ß maturation, indicating NLRP3 inflammasome activation. Compared with m-CSF differentiated macrophages only gm-CSF differentiated macrophages expressed macrophage elastase (MMP12) and METs released by the latter had significantly more bactericidal activity toward E. coli. Mechanistically, phospholipase C and peptidyl arginine deiminase-2 inhibition attenuate MET release. Interestingly, NLRP3 inflammasome blockade by MCC950 had a significant effect on MET release. Finally, MET release was completely blocked by plasma membrane stabilization by punicalagin. Altogether, we demonstrate that extracellular calcium-activated hMDM extrude DNA, containing citrullinated histones, MPO, MMP12, and ASC specks and released METs kill bacteria independent of hMDM phagocytotic activity. We believe that calcium-activated hMDM adds a physiologically relevant condition to calcium ionophore induced cell death that may be important in autoimmunity.

Abstract Image

PLC和PAD2调控细胞外钙触发巨噬细胞释放细胞外DNA陷阱
巨噬细胞可以通过形成炎性小体或通过METosis释放DNA的细胞外陷阱(et)来应对感染或细胞应激。虽然et在中性粒细胞中已被广泛研究,但对METosis的研究较少。我们发现,细胞外钙和LPS使人单核细胞源性巨噬细胞(hMDM)释放带有髓过氧化物酶(MPO)和葡氨酸化组蛋白修饰的细胞外DNA,同时伴有ASC聚集和IL-1ß成熟,表明NLRP3炎性体激活。与m-CSF分化的巨噬细胞相比,gm-CSF分化的巨噬细胞仅表达巨噬细胞弹性酶(MMP12),后者释放的METs对大肠杆菌的杀菌活性显著增强。从机制上讲,磷脂酶C和肽基精氨酸脱亚胺酶-2抑制可减弱MET的释放。有趣的是,MCC950阻断NLRP3炎性体对MET释放有显著影响。最后,甘蔗渣的质膜稳定作用完全阻断了MET的释放。总之,我们证明了细胞外钙激活的hMDM挤出含有瓜氨酸化组蛋白、MPO、MMP12和ASC斑点的DNA,并释放出独立于hMDM吞噬活性的METs杀死细菌。我们认为钙激活的hMDM为钙离子载体诱导的细胞死亡增加了一个生理相关条件,这可能在自身免疫中很重要。
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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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