Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.

巨噬细胞在肠道免疫中发挥着核心作用，但不适当的巨噬细胞激活与炎症性肠病（IBD）有关。在这里，我们确定粒细胞巨噬细胞集落刺激因子（GM-CSF）是 IBD 患者和右旋糖酐硫酸钠（DSS）诱导的结肠炎小鼠肠道巨噬细胞激活的关键调节因子。我们发现 GM-CSF 驱动炎症性肠道巨噬细胞的成熟和极化，促进抗菌功能，同时抑制伤口愈合转录程序。第 3 组先天淋巴细胞 (ILC3) 是肠道炎症中 GM-CSF 的主要来源，在 IBD 粘膜活检中观察到 ILC 或CSF2转录物与 M1 巨噬细胞特征之间存在很强的正相关性。此外，GM-CSF 依赖性巨噬细胞极化会导致正反馈回路，从而增强 ILC3 激活和 17 型免疫。总之，我们的数据揭示了 GM-CSF 介导的 ILC-巨噬细胞串扰在校准肠道巨噬细胞表型以增强抗菌反应中的重要作用，同时抑制与纤维化和狭窄相关的促修复功能，具有重要的临床意义。