Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.
Macrophage programming is regulated by a cooperative interaction between fatty acid binding protein 5 and peroxisome proliferator-activated receptor γ.
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DOI：
10.1096/fj.202200128r
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发表时间：
2022-05
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影响因子：
--
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中科院分区：
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炎症的消退是一个积极的过程，受到严格的调节，以实现修复和组织稳态。在没有解决的情况下，持续性炎症是慢性肺病（如慢性阻塞性肺病（COPD））复发性加重的发病机制的基础。在炎症过程中，巨噬细胞编程从促炎转变为促消退，这部分受到核受体过氧化物酶体激活受体γ（PPARγ）的调节。我们以前的工作证明了健康和COPD患者外周血单个核细胞中脂肪酸结合蛋白5（FABP 5）表达与PPARγ活性之间的相关性。然而，FABP 5在巨噬细胞编程中的作用尚未被研究。在这里，使用体外和体内方法的组合，我们证明了FABP 5是必要的PPARγ激活。反过来，PPARγ直接作用于增加原代人肺泡巨噬细胞中的FABP 5表达。我们进一步说明，FABP 5表达的缺乏促进促炎巨噬细胞编程，促炎细胞因子的分泌增加，促炎转录因子的染色质可及性增加（例如，NF-κB和MAPK）。最后，使用Seahorse技术进行的真实的时间细胞代谢分析显示，FABP 5缺陷型巨噬细胞中的氧化磷酸化受到抑制。总之，我们的数据表明，FABP 5和PPARγ γ调节彼此的表达和功能，这与介导巨噬细胞促分解编程的两个因子之间的新型正反馈回路一致。我们的研究强调了确定控制炎症消退的靶点和调节机制的重要性，并可能为针对COPD的新型干预策略提供信息。
Resolution of inflammation is an active process that is tightly regulated to achieve repair and tissue homeostasis. In the absence of resolution, persistent inflammation underlies the pathogenesis of chronic lung disease such as chronic obstructive pulmonary disease (COPD) with recurrent exacerbations. Over the course of inflammation, macrophage programming transitions from pro‐inflammatory to pro‐resolving, which is in part regulated by the nuclear receptor Peroxisome Proliferator‐Activated Receptor γ (PPARγ). Our previous work demonstrated an association between Fatty Acid Binding Protein 5 (FABP5) expression and PPARγ activity in peripheral blood mononuclear cells of healthy and COPD patients. However, a role for FABP5 in macrophage programming has not been examined. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FABP5 is necessary for PPARγ activation. In turn, PPARγ acts directly to increase FABP5 expression in primary human alveolar macrophages. We further illustrate that lack of FABP5 expression promotes a pro‐inflammatory macrophage programming with increased secretion of pro‐inflammatory cytokines and increased chromatin accessibility for pro‐inflammatory transcription factors (e.g., NF‐κB and MAPK). And finally, real‐time cell metabolic analysis using the Seahorse technology shows an inhibition of oxidative phosphorylation in FABP5‐deficient macrophages. Taken together, our data indicate that FABP5 and PPARγ reciprocally regulate each other's expression and function, consistent with a novel positive feedback loop between the two factors that mediates macrophage pro‐resolving programming. Our studies highlight the importance of defining targets and regulatory mechanisms that control the resolution of inflammation and may serve to inform novel interventional strategies directed towards COPD.
影响因子：
3.7
作者：
Green RM;Gally F;Keeney JG;Alper S;Gao B;Han M;Martin RJ;Weinberger AR;Case SR;Minor MN;Chu HW
通讯作者：
Chu HW