Scholarlink

Background <p>Pulmonary fibrosis (PF) is an irreversible and lethal lung disease characterized by progressive scarring lacking safe and effective treatment options. Recent studies have underscored the role of macrophage polarization in fibrotic progression, yet the role of kynurenine (Kyn), a metabolite of tryptophan (Trp), in macrophages during PF progression remains elusive.</p> Methods <p>Liquid Chromatography–tandem Mass Spectrometry (LC–MS) analysis was used to detect tryptophan metabolism changes in the serum of PF patients and control subjects. Macrophage-specific <i>Ido1</i> or <i>Ahr</i> deletion mice was utilized to explored the role of Kyn in the bleomycin-induced fibrotic mouse model and ChIP sequence was employed to elucidate the mechanism by which Kyn inhibits pro-fibrotic macrophage activation.</p> Results <p>We identified Kyn, Trp levels and Kyn/Trp ratio (KTR) were notably elevated in the serum of patients with different types of PF and these alterations were inversely correlated with lung function. Although such elevation might appear pathogenic, our functional studies demonstrate that Kyn exerts protective effects in PF, akin to brain natriuretic peptide in heart failure. Macrophage-specific deletion of <i>Ido1</i> or aryl hydrocarbon receptor (<i>AhR</i>, the receptor of Kyn) exacerbated bleomycin-induced PF, while exogenous Kyn supplementation mitigated disease severity. Mechanistically, Kyn bound to the AhR, facilitating its nuclear translocation, where it promoted Slc39a10 transcription to increase the intracellular levels of zinc ion, thereby inhibiting profibrotic macrophage differentiation. Intriguingly, pirfenidone was noted with high potency to suppress Kyn production and our studies demonstrated that administration of Kyn along with pirfenidone effectively enhanced the therapeutic efficacy against PF.</p> Conclusions <p>In summary, these findings reveal a previously unrecognized Kyn-AhR-SLC39A10-Zn<sup>2+</sup> signaling axis that governs macrophage polarization in PF, and unveiled the importance of Trp metabolism in PF pathogenesis, which could be novel therapeutic strategies against PF.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Kynurenine-AhR-SLC39A10-Zn2+ signaling reprograms macrophages and enhances pirfenidone efficacy in pulmonary fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月30日

查看全文
  • Huihui Yue,
  • Ruihan Dong,
  • Jianhan He,
  • Fengqin Zhang,
  • Yan Fan,
  • Xinran Dou,
  • Qing Zhou,
  • Xuan Li,
  • Long He,
  • Shu Zhang,
  • Qilin Yu,
  • Weikuan Gu,
  • Jianping Zhao,
  • Yi Wang,
  • Cong-Yi Wang,
  • Huilan Zhang

摘要

Background

Pulmonary fibrosis (PF) is an irreversible and lethal lung disease characterized by progressive scarring lacking safe and effective treatment options. Recent studies have underscored the role of macrophage polarization in fibrotic progression, yet the role of kynurenine (Kyn), a metabolite of tryptophan (Trp), in macrophages during PF progression remains elusive.

Methods

Liquid Chromatography–tandem Mass Spectrometry (LC–MS) analysis was used to detect tryptophan metabolism changes in the serum of PF patients and control subjects. Macrophage-specific Ido1 or Ahr deletion mice was utilized to explored the role of Kyn in the bleomycin-induced fibrotic mouse model and ChIP sequence was employed to elucidate the mechanism by which Kyn inhibits pro-fibrotic macrophage activation.

Results

We identified Kyn, Trp levels and Kyn/Trp ratio (KTR) were notably elevated in the serum of patients with different types of PF and these alterations were inversely correlated with lung function. Although such elevation might appear pathogenic, our functional studies demonstrate that Kyn exerts protective effects in PF, akin to brain natriuretic peptide in heart failure. Macrophage-specific deletion of Ido1 or aryl hydrocarbon receptor (AhR, the receptor of Kyn) exacerbated bleomycin-induced PF, while exogenous Kyn supplementation mitigated disease severity. Mechanistically, Kyn bound to the AhR, facilitating its nuclear translocation, where it promoted Slc39a10 transcription to increase the intracellular levels of zinc ion, thereby inhibiting profibrotic macrophage differentiation. Intriguingly, pirfenidone was noted with high potency to suppress Kyn production and our studies demonstrated that administration of Kyn along with pirfenidone effectively enhanced the therapeutic efficacy against PF.

Conclusions

In summary, these findings reveal a previously unrecognized Kyn-AhR-SLC39A10-Zn2+ signaling axis that governs macrophage polarization in PF, and unveiled the importance of Trp metabolism in PF pathogenesis, which could be novel therapeutic strategies against PF.