IgA2 ACPA Drives a Hyper-Inflammatory Phenotype in Macrophages via ATP Synthase and COX2

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Luís Almeida, Alice Bacon, Mohan Ghorasaini, Alwin J. van der Ham, René E. M. Toes, Martin Giera, Bart Everts
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Abstract

IgA can form immune complexes (ICs) and activate myeloid cells via Fc alpha receptor-mediated signalling to secrete pro-inflammatory cytokines. It was previously described that of the two IgA subclasses (IgA1 and IgA2), IgA2 is more inflammatory than IgA1. However, the mechanisms underlying this differential pro-inflammatory potential remain poorly defined. Using anti-citrullinated protein IgA1 and IgA2 antibodies (ACPA) that are commonly found in rheumatoid arthritis (RA) patients and linked to chronic inflammation, we show here that, in macrophages, IgA2-ICs boost TLR-induced TNF and IL6 secretion, COX2 expression, and production of COX2-dependent lipid mediators to a higher level than IgA1-ICs. Metabolically, we found the amplification of TLR-induced cytokine production and COX2 induction by IgA2-ICs to be dependent on mitochondrial ATP synthesis, but not glycolysis. Finally, we found the potentiation of TLR-induced cytokine production by IgA-ICs to be COX2-dependent. Together this work points towards a key role for mitochondrial ATP synthesis in driving COX2 expression and subsequent IgA2-IC-dependent potentiation of TLR-induced cytokine production by macrophages. As such, our work provides new insights into the mechanisms underlying IgA2-induced inflammation in the context of RA. Thus, this may hold novel clues to be explored as therapeutic possibilities to target antibody-driven inflammation in chronic inflammatory diseases.

Abstract Image

IgA2 ACPA通过ATP合酶和COX2驱动巨噬细胞的高炎症表型
IgA可以形成免疫复合物(ic),并通过Fc α受体介导的信号传导激活髓细胞,分泌促炎细胞因子。先前有报道称,在两种IgA亚类(IgA1和IgA2)中,IgA2比IgA1更具炎症性。然而,这种不同促炎潜能背后的机制仍然不明确。使用抗瓜氨酸化蛋白IgA1和IgA2抗体(ACPA),这些抗体常见于类风湿性关节炎(RA)患者并与慢性炎症相关,我们在这里发现,在巨噬细胞中,IgA2- ic可以将tlr诱导的TNF和IL6分泌、COX2表达和COX2依赖性脂质介质的产生提高到比IgA1- ic更高的水平。在代谢方面,我们发现tlr诱导的细胞因子产生和iga2 - ic诱导的COX2扩增依赖于线粒体ATP合成,而不是糖酵解。最后,我们发现iga - ic对tlr诱导的细胞因子产生的增强是依赖于cox - 2的。总之,这项工作指出了线粒体ATP合成在驱动COX2表达和随后的iga2 - ic依赖性tlr诱导巨噬细胞产生细胞因子的增强中的关键作用。因此,我们的工作为类风湿关节炎中iga2诱导炎症的机制提供了新的见解。因此,这可能为慢性炎症性疾病中靶向抗体驱动炎症的治疗可能性提供新的线索。
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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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