O'Brien Eóin C, White Carla A, Wyse Jason, Leacy Emma, Porter Richard K, Little Mark A, Hickey Fionnuala B
Department of Clinical Medicine, Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland.
Discipline of Statistics and Information Systems, School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland.
Front Med (Lausanne). 2020 Sep 8;7:553. doi: 10.3389/fmed.2020.00553. eCollection 2020.
Clinical and experimental data suggest that pathogenesis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is driven by ANCA-mediated activation of neutrophils and monocytes. While the role of neutrophils has been extensively investigated, the function of monocytes remains relatively understudied. We have previously demonstrated that stimulation of monocytes with anti-myeloperoxidase (MPO), but not anti-proteinase-3 (PR3), antibodies results in production of the pro-inflammatory cytokine IL-1β. Changes in cellular metabolism, particularly a switch to glycolysis, have recently been linked to activation of immune cells and production of IL-1β. Therefore, we investigated the metabolic profile of monocytes following ANCA stimulation. We found a significant increase in glucose uptake in anti-MPO stimulated monocytes. Interestingly, both anti-MPO and anti-PR3 stimulation resulted in an immediate increase in glycolysis, measured by Seahorse extracellular flux analysis. However, this increase in glycolysis was sustained (for up to 4 h) in anti-MPO- but not anti-PR3-treated cells. In addition, only anti-MPO-treated cells exhibited increased oxidative phosphorylation, a metabolic response that correlated with IL-1β production. These data indicate that monocyte metabolism is altered by ANCA, with divergent responses to anti-MPO and anti-PR3 antibodies. These metabolic changes may underlie pathologic immune activation in ANCA associated vasculitis, as well as potentially contributing to the differing clinical phenotype between PR3- and MPO-ANCA positive patients. These metabolic pathways may therefore be potential targets for therapeutic intervention.
临床和实验数据表明，抗中性粒细胞胞浆抗体（ANCA）相关血管炎的发病机制是由ANCA介导的中性粒细胞和单核细胞激活所驱动。虽然中性粒细胞的作用已得到广泛研究，但单核细胞的功能仍相对研究较少。我们之前已经证明，用抗髓过氧化物酶（MPO）而非抗蛋白酶3（PR3）抗体刺激单核细胞会导致促炎细胞因子IL-1β的产生。细胞代谢的变化，特别是向糖酵解的转变，最近已与免疫细胞的激活和IL-1β的产生联系起来。因此，我们研究了ANCA刺激后单核细胞的代谢特征。我们发现抗MPO刺激的单核细胞中葡萄糖摄取显著增加。有趣的是，通过海马细胞外通量分析测量，抗MPO和抗PR3刺激均导致糖酵解立即增加。然而，这种糖酵解的增加在抗MPO处理的细胞中持续（长达4小时），而在抗PR3处理的细胞中则没有。此外，只有抗MPO处理的细胞表现出氧化磷酸化增加，这是一种与IL-1β产生相关的代谢反应。这些数据表明，ANCA会改变单核细胞代谢，对抗MPO和抗PR3抗体有不同反应。这些代谢变化可能是ANCA相关血管炎中病理性免疫激活的基础，也可能导致PR3-ANCA和MPO-ANCA阳性患者临床表型的差异。因此，这些代谢途径可能是治疗干预的潜在靶点。
