Necrotizing enterocolitis (NEC) is a form of potentially lethal gastrointestinal inflammation that primarily affects preterm neonates. It is crucial to recognize that, while the disease carries significant risks, timely and effective medical intervention can greatly enhance the chances of survival. Additionally, NEC is closely linked to the activation of macrophages, highlighting the complex interplay between the immune response and disease progression. CD38, acting as an ectoenzyme, catalyzes the hydrolysis of NAD+ to produce cyclic ADP-ribose (cADPR), a reaction critical for modulating cellular redox balance and energy homeostasis. This enzymatic activity is particularly pertinent in the context of necrotizing enterocolitis (NEC). In this research, we investigated whether CD38 deletion can elevate NAD+ levels to reduce macrophage-mediated inflammation and improve NEC severity. We show that NEC patients was associated with the increased CD38 expression in intestine and blood. These results were also observed in NEC mice, and CD38 deletion ameliorated NEC intestinal injury. Mechanistically, CD38 deletion elevated NAD+ levels that reduced oxidative stress and intestinal inflammation. Furthermore, CD38 deletion promoted M2 macrophage polarization, inhibited macrophage activation and phagocytosis ability. Thus, our results reveal a critical role for CD38 as an intracellular immune regulator for regulating macrophage activation and intestinal inflammation in NEC. Targeting CD38 and NAD+ signal maybe a promising strategy for treatment of NEC.

中文翻译：

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在实验环境中，CD38 的缺失通过调节巨噬细胞介导的炎症来减轻 NEC 的严重程度


坏死性小肠结肠炎 （NEC） 是一种可能致命的胃肠道炎症，主要影响早产新生儿。重要的是要认识到，虽然这种疾病具有重大风险，但及时有效的医疗干预可以大大提高生存机会。此外，NEC 与巨噬细胞的激活密切相关，突出了免疫反应与疾病进展之间的复杂相互作用。CD38 作为一种胞外酶，催化 NAD+ 水解产生环状 ADP-核糖 （cADPR），这是一种对调节细胞氧化还原平衡和能量稳态至关重要的反应。这种酶活性在坏死性小肠结肠炎 （NEC） 的情况下特别相关。在这项研究中，我们研究了 CD38 缺失是否可以提高 NAD+ 水平以减少巨噬细胞介导的炎症并改善 NEC 的严重程度。我们表明 NEC 患者与肠道和血液中 CD38 表达的增加有关。在 NEC 小鼠中也观察到这些结果，CD38 缺失改善了 NEC 肠道损伤。从机制上讲，CD38 缺失提高了 NAD+ 水平，从而减少了氧化应激和肠道炎症。此外，CD38 缺失促进 M2 巨噬细胞极化，抑制巨噬细胞活化和吞噬能力。因此，我们的结果揭示了 CD38 作为细胞内免疫调节因子在 NEC 中调节巨噬细胞活化和肠道炎症的关键作用。靶向 CD38 和 NAD+ 信号可能是治疗 NEC 的一种有前途的策略。