Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-15 DOI:10.1172/jci.insight.181686
Xin Yu, Yujing Song, Tao Dong, Wenlu Ouyang, Liujiazi Shao, Chao Quan, Kyung Eun Lee, Tao Tan, Allan Tsung, Katsuo Kurabayashi, Hasan B Alam, Mao Zhang, Jianjie Ma, Yongqing Li
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Abstract

Sepsis-induced acute lung injury (ALI) is prevalent in septic patients and has a high mortality rate. Peptidyl arginine deiminase (PADI) 2 and PADI4 play crucial roles in mediating the host's immune response in sepsis, but their specific functions remain unclear. Our study shows that Padi2-/-Padi4-/- double knockout (DKO) improved survival, reduced lung injury, decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia-induced sepsis mice. Using single-cell RNA sequencing (scRNA-seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3+ pro-inflammatory macrophages and fostered Chil3+ myeloid cell differentiation into anti-inflammatory macrophages. Additionally, we observed the regulatory role of NLRP3-Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3 KO experiments. Thus, eliminating Padi2 and Padi4 enhances the polarization of Ym1+ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. study unveils the PADI2/PADI4-NLRP3-Ym1 pathway as a potential target in treatment of sepsis-induced ALI.

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通过抑制 NLRP3+ 巨噬细胞,缺失 PADI2 和 PADI4 可改善败血症诱发的急性肺损伤。
脓毒症引起的急性肺损伤(ALI)在脓毒症患者中很常见,而且死亡率很高。肽基精氨酸脱氨酶(PADI)2和PADI4在脓毒症中介导宿主免疫反应方面起着至关重要的作用,但它们的具体功能仍不清楚。我们的研究表明,Padi2-/-Padi4-/-双基因敲除(DKO)提高了铜绿假单胞菌(PA)肺炎诱导的脓毒症小鼠的存活率,减少了肺损伤,降低了细菌负荷。通过单细胞 RNA 测序(scRNA-seq),我们发现 Padi2 和 Padi4 的缺失会减少 Nlrp3+ 促炎巨噬细胞,并促进 Chil3+ 髓系细胞分化为抗炎巨噬细胞。此外,我们通过 Chil3 敲除和 Nlrp3 KO 实验证实了 DKO 对 NLRP3-Ym1 轴的调控作用。因此,消除 Padi2 和 Padi4 可通过抑制 NLRP3 增强 Ym1+ M2 巨噬细胞的极化,从而帮助炎症消退和肺组织修复。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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