Abstract
Iron plays an important role in macrophage polarization by altering metabolic and redox status. However, the impact of iron on the immune status of macrophages is still controversial. In this study, we report that ferric ammonium citrate (FAC) upregulates PD-L1 expression in macrophages. FAC not only altered the phenotype of macrophages but also led to enriching immune-modulatory T cell subsets. Since iron is known to be a constituent of coenzymes facilitating metabolic processes in mitochondria, we examined the metabolic status of FAC-overloaded macrophages by measuring the oxygen consumption rate (OCR) and the represented coenzyme, aconitase. In addition to enhancement of metabolic processes, FAC accelerated the Fenton reaction in macrophages, which also contributed to the facilitation of oxygen consumption. We reasoned that the enhancement of the OCR leads to the production of reactive oxygen species (ROS), which are directly linked to PD-L1 induction. Using ferrostatin, rotenone, and N-acetyl-L-cysteine, we confirmed that metabolic and redox regulation is responsible for FAC-mediated PD-L1 expression. Furthermore, we suggested that FAC-induced ROS production may explain FAC-mediated pro- and anti-inflammatory responses in macrophages. These findings may extend our understanding of regulating iron concentration during immune checkpoint therapy in cancer patients.
Highlights
Macrophages play key roles in regulating the innate and adaptive immune systems in response to environmental milieu by polarizing toward either M1 or M2 macrophages [1]
To confirm the role of ferric ammonium citrate (FAC) in macrophage polarization, we first investigated the change in the expression of costimulatory molecules in macrophages
We examined whether reactive oxygen species (ROS) produced by FAC-mediated oxidative phosphorylation (OXPHOS) and the Fenton reaction is responsible for IL-1β and PD-L1 expression
Summary
Macrophages play key roles in regulating the innate and adaptive immune systems in response to environmental milieu by polarizing toward either M1 (classically activated) or M2 (alternatively activated) macrophages [1]. Metabolic reprogramming in macrophages is an important factor in determining such polarization status [2,3,4,5]. Upon exposure to a trigger, a naïve macrophage polarizes into M1 by turning on proinflammatory processes, including the expression of costimulatory molecules and the production of cytokines. The reduced flux in turn generates two metabolic breaks in mitochondria, which leads to the accumulation of citrate and succinate [4, 6]. The accumulation of citrate facilitates the lipid membrane expansion that is essential for the transportation and secretion of cytokines; the excess succinate aggravates hypoxiainduced factor 1α- (HIF1α-) mediated inflammation, which helps sustain M1 status [6, 9]. M2 macrophages predominantly produce energy via OXPHOS by facilitating TCA flux in mitochondria [10]. The expression of PDL1, one of the costimulatory molecules that promotes polarization toward M2, requires OXPHOS-dominant metabolic reprogramming [11,12,13]
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