炎症
车站3
信号转导
转化生长因子
细胞生物学
癌症研究
化学
免疫学
医学
生物
作者
Zhigang Lei,Rui Tang,Wu Yu,Chunyou Mao,Weijie Xue,Jian-fan Shen,Jiaojiao Yu,Xiaohong Wang,Xin Qi,Chuan Wei,Lei Xu,Jun Zhu,Yalin Li,Xiujun Zhang,Chunyan Ye,Xiaojun Chen,Xiaojun Yang,Sha Zhou,Chuan Su
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-03-05
卷期号:9 (7)
标识
DOI:10.1172/jci.insight.165544
摘要
Programmed cell death protein 1 (PD-1), a coinhibitory T-cell checkpoint, is also expressed on macrophages (Mφ) in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on Mφ for dampening immune responses. However, the mechanism governing PD-1 expression in Mφ in chronic inflammation remains largely unknown. TGF-β1 (transforming growth factor-β1) is abundant within chronic inflammatory microenvironments. Here, based on public databases, significant positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, Mφ as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and S. japonicum infection were used as experimental models for chronic inflammation. PD-1hi Mφ from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-β receptors. Either TGF-β1-neutralizing antibody administration or Mφ-specific Tgfbr1 knockdown largely reduced PD-1 expression on Mφ in animal models. We further demonstrated that TGF-β1 directly induced PD-1 expression on Mφ. Mechanistically, TGF-β1-induced PD-1 expression on Mφ was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that Mφ adapt to chronic inflammation through TGF-β1-triggered cooperative SMAD3-STAT3 signaling that induces PD-1 expression and modulates Mφ function.
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