Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this “balancing act” remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a “default” Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.

活化的巨噬细胞必须仔细校准它们的炎症反应，以平衡有效的病原体控制与炎症介导的组织损伤，但这种“平衡行为”的分子基础仍不清楚。使用基因工程小鼠模型和原代巨噬细胞培养物，我们发现 Toll 样受体 (TLR) 信号通过核因子 κB (NF-κB) 依赖性机制在巡逻单核细胞和组织巨噬细胞中选择性地诱导转录因子Spic的表达。在功能上，Spic通过调节活化巨噬细胞中的铁转运蛋白表达来下调促炎细胞因子并促进铁流出。值得注意的是，干扰素-γ 阻断Spic以依赖于 STAT1 的方式表达。高水平的干扰素-γ 表示持续感染，如果没有，活化的巨噬细胞似乎会参与“默认” Spic依赖性抗炎途径。我们还提供了该通路参与无菌炎症的证据。综上所述，我们的研究结果揭示了一条途径，其中 NF-κB 和 STAT 对Spic的反调节调节巨噬细胞中的炎症反应和铁代谢。