Division of Allergy & Immunology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
Front Immunol. 2024 Sep 16;15:1432334. doi: 10.3389/fimmu.2024.1432334. eCollection 2024.
Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung disease. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Aconitate decarboxylase 1 () was one of the most upregulated genes following LPS (vs. saline) exposure of murine whole lungs with transcriptomic profiling of sorted lung monocyte/macrophage subpopulations also highlighting its significance. Given monocyte/macrophage activation can be tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator ACOD1 in environmental exposure-induced lung inflammation.
Wild-type (WT) mice were intratracheally (i.t.) instilled with 10 μg of LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 h post-exposure. Next, WT and mice were instilled with LPS, 25% organic dust extract (ODE), or saline, whereupon serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Invasive lung function testing was performed 3 h post-LPS with WT and mice.
mice treated with LPS demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4 T cells, decreased BALF and lung levels of TNF-α, and decreased BALF CXCL1 compared to WT animals. In comparison, mice treated with ODE demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B-cell infiltrates with decreased BALF levels of TNF-α and IL-6 and decreased lung CXCL1 vs. WT animals. Mediators of tissue remodeling (TIMP1, MMP-8, MMP-9) were also decreased in the LPS-exposed mice, with MMP-9 also reduced in ODE-exposed mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyperresponsiveness in animals.
is robustly upregulated in the lungs following LPS exposure and encodes a key immunometabolic regulator. ACOD1 mediates the proinflammatory response to acute inhaled environmental LPS and organic dust exposure-induced lung inflammation.
环境脂多糖 (LPS) 和富含微生物成分的有机尘埃会导致严重的肺部疾病。这些环境暴露会招募和激活参与疾病发病机制的不同肺单核细胞/巨噬细胞亚群。乙酰辅酶 A 脱羧酶 1 (ACOD1) 是 LPS（与盐水）暴露后鼠全肺转录组分析中上调最明显的基因之一，对分选的肺单核细胞/巨噬细胞亚群的分析也突出了其重要性。鉴于单核细胞/巨噬细胞的激活可以与代谢紧密相关，这些研究的目的是确定免疫代谢调节剂 ACOD1 在环境暴露诱导的肺部炎症中的作用。
野生型 (WT) 小鼠通过气管内 (i.t.) 滴注 10 μg LPS 或盐水。使用批量 RNA 测序或分选来分离单核细胞/巨噬细胞亚群，对全肺进行分析。在暴露后 48 小时，通过 NanoString 先天免疫多plex 阵列对分选的亚群进行转录组特征分析。接下来，WT 和 小鼠被滴注 LPS、25%有机尘埃提取物 (ODE) 或盐水，随后收集血清、支气管肺泡灌洗液 (BALF) 和肺组织。通过质谱法定量三羧酸 (TCA) 循环中的代谢物。通过 ELISA 定量细胞因子/趋化因子和组织重塑介质。通过流式细胞术对肺免疫细胞进行表征。WT 和 小鼠在 LPS 处理后 3 小时进行肺功能侵入性检测。
用 LPS 处理的 小鼠的 BALF 中异枸橼酸水平降低，TCA 循环重编程，BALF 中性粒细胞减少，肺 CD4 T 细胞增加，BALF 和肺 TNF-α 水平降低，BALF CXCL1 水平降低与 WT 动物相比。相比之下，ODE 处理的 小鼠的血清 pentraxin-2、BALF 中的异枸橼酸、肺总细胞、中性粒细胞、单核细胞和 B 细胞浸润减少，BALF 中的 TNF-α 和 IL-6 水平降低，肺 CXCL1 水平降低与 WT 动物相比。LPS 暴露的 小鼠中组织重塑介质 (TIMP1、MMP-8、MMP-9) 也减少，ODE 暴露的 小鼠中 MMP-9 也减少。LPS 诱导的气道高反应性的肺功能评估表明， 小鼠的反应减弱。
在 LPS 暴露后，ACOD1 在肺部中被强烈上调，并编码关键的免疫代谢调节剂。ACOD1 介导急性吸入环境 LPS 和有机尘埃暴露诱导的肺部炎症的促炎反应。
