Almeida Luís, Bacon Alice, Ghorasaini Mohan, van der Ham Alwin J, Toes René E M, Giera Martin, Everts Bart
Centre for Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
Eur J Immunol. 2025 Apr;55(4):e202451586. doi: 10.1002/eji.202451586.
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.
IgA可形成免疫复合物（ICs），并通过Fcα受体介导的信号传导激活髓样细胞，以分泌促炎细胞因子。先前有描述称，在两种IgA亚类（IgA1和IgA2）中，IgA2比IgA1更具炎症性。然而，这种不同的促炎潜力背后的机制仍不清楚。使用类风湿性关节炎（RA）患者中常见且与慢性炎症相关的抗瓜氨酸化蛋白IgA1和IgA2抗体（ACPA），我们在此表明，在巨噬细胞中，IgA2-ICs比IgA1-ICs更能促进TLR诱导的TNF和IL6分泌、COX2表达以及COX2依赖性脂质介质的产生。在代谢方面，我们发现IgA2-ICs对TLR诱导的细胞因子产生和COX2诱导的放大作用依赖于线粒体ATP合成，而非糖酵解。最后，我们发现IgA-ICs对TLR诱导的细胞因子产生的增强作用是COX2依赖性的。这项工作共同表明线粒体ATP合成在驱动COX2表达以及随后巨噬细胞对TLR诱导的细胞因子产生的IgA2-IC依赖性增强中起关键作用。因此，我们的工作为RA背景下IgA2诱导炎症的机制提供了新的见解。因此，这可能为探索作为治疗慢性炎症性疾病中抗体驱动炎症的治疗可能性提供新线索。
