Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.

专门限制炎症免疫细胞破坏潜力的转录因子仍然不明确。我们在多名不相关的男性患者中发现了 X 连锁 ETS 转录因子基因ELF4的功能丧失变异，这些患者具有早发性粘膜自身炎症和炎症性肠病 (IBD) 特征，包括对白细胞介素 1 (IL-1) 有反应的发烧和溃疡。 1）、肿瘤坏死因子或IL-12p40阻断。使用来自患者的细胞和新生成的小鼠模型，我们发现 ELF4 突变巨噬细胞对一系列先天刺激具有过度炎症反应。在小鼠巨噬细胞中，Elf4 既能维持Il1rn等抗炎基因的表达，又能限制S100A8 、 Lcn2 、 Trem1和中性粒细胞趋化因子等炎症放大器的上调。在携带患者源性 Elf4 变异的小鼠体内进行脂多糖攻击后，阻断 Trem1 可逆转炎症和肠道病理。因此，ELF4 可以抑制炎症并预防粘膜疾病，这一发现与 IBD 等人类炎症性疾病具有广泛的转化相关性。