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<p>Necrotizing enterocolitis (NEC) is a severe inflammatory condition that affects premature infants, marked by intestinal necrosis and systemic inflammation. This study examined interleukin-40 (IL-40) levels in patients with NEC and investigated its influence on inflammation, neutrophil function, and the formation of neutrophil extracellular traps (NET) using clinical samples and experimental models. Intestinal tissue samples were obtained from infants diagnosed with NEC and from control subjects, with plasma IL-40 levels subsequently measured. An experimental NEC model was established employing IL-40 knockout (IL-40−/−) and wild-type (WT) mice to assess the effects of IL-40 deficiency on disease progression. Results indicated that IL-40 levels were significantly elevated in NEC patients compared to controls, correlating with enhanced NET formation and greater disease severity. In the murine model, IL-40−/− mice demonstrated reduced NEC severity, lower neutrophil infiltration, and diminished NET release. Mechanistic studies indicated that the absence of IL-40 decreased mitochondrial reactive oxygen species (ROS) production and the release of oxidized mitochondrial DNA (ox-mtDNA), both crucial for NET formation. In conclusion, this study highlights the significant role of IL-40 in NEC by promoting neutrophil activation and NETosis. Targeting IL-40 may present a promising therapeutic approach to mitigate intestinal damage in NEC by inhibiting NETosis and reducing inflammation.</p> Graphical Abstract <p></p>

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Deficiency of interleukin-40 prevents intestinal damage in experimental necrotizing enterocolitis by inhibiting NETosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月7日

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  • Yunfei Zhang,
  • Cuilian Ye,
  • Xin Zhong,
  • Xionghui Ding,
  • Yihang Yang,
  • Yue Ma,
  • Chunbao Guo

摘要

Necrotizing enterocolitis (NEC) is a severe inflammatory condition that affects premature infants, marked by intestinal necrosis and systemic inflammation. This study examined interleukin-40 (IL-40) levels in patients with NEC and investigated its influence on inflammation, neutrophil function, and the formation of neutrophil extracellular traps (NET) using clinical samples and experimental models. Intestinal tissue samples were obtained from infants diagnosed with NEC and from control subjects, with plasma IL-40 levels subsequently measured. An experimental NEC model was established employing IL-40 knockout (IL-40−/−) and wild-type (WT) mice to assess the effects of IL-40 deficiency on disease progression. Results indicated that IL-40 levels were significantly elevated in NEC patients compared to controls, correlating with enhanced NET formation and greater disease severity. In the murine model, IL-40−/− mice demonstrated reduced NEC severity, lower neutrophil infiltration, and diminished NET release. Mechanistic studies indicated that the absence of IL-40 decreased mitochondrial reactive oxygen species (ROS) production and the release of oxidized mitochondrial DNA (ox-mtDNA), both crucial for NET formation. In conclusion, this study highlights the significant role of IL-40 in NEC by promoting neutrophil activation and NETosis. Targeting IL-40 may present a promising therapeutic approach to mitigate intestinal damage in NEC by inhibiting NETosis and reducing inflammation.

Graphical Abstract