Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response
Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response
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DOI：
10.1016/j.celrep.2020.01.030
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发表时间：
2020-02-11
期刊：
影响因子：
8.8
通讯作者：
Spath, Gerald F.
中科院分区：
文献类型：
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作者：
Lecoeur, Herve;Prina, Eric;Spath, Gerald F.
细胞内感染期间异常的巨噬细胞活化产生可引起严重人类发病的免疫病理学。更好地了解免疫颠覆策略和巨噬细胞表型和功能反应是必要的，以设计主机定向干预策略。在这里，我们发现了一个微调的转录反应，诱导在原发性和病变巨噬细胞感染的寄生虫亚马逊利什曼原虫和抑制NF-κ B和NLRP 3炎性体激活。颠覆是无鞭毛体特异性的，其特征在于这些促炎途径的活化组分的表达降低和失活组分的表达增加，从而揭示了废除抗微生物反应的调节二分法。转录本丰度的变化与感染的原发性和病变巨噬细胞中NF-κ B相关促炎基因启动子处的组蛋白H3 K9/14低乙酰化和H3 K4低三甲基化相关。我们的研究结果揭示了利什曼原虫免疫颠覆策略，靶向宿主细胞表观遗传调控，以建立有利于寄生虫生存的条件，并为宿主导向的抗微生物药物发现开辟了途径。
Aberrant macrophage activation during intracellular infection generates immunopathologies that can cause severe human morbidity. A better understanding of immune subversion strategies and macrophage phenotypic and functional responses is necessary to design host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response that is induced in primary and lesional macrophages infected by the parasite Leishmania amazonensis and dampens NF-kappa B and NLRP3 inflammasome activation. Subversion is amastigote-specific and characterized by a decreased expression of activating and increased expression of de-activating components of these pro-inflammatory pathways, thus revealing a regulatory dichotomy that abrogates the anti-microbial response. Changes in transcript abundance correlate with histone H3K9/14 hypoacetylation and H3K4 hypo-trimethylation in infected primary and lesional macrophages at promoters of NF-kappa B-related, pro-inflammatory genes. Our results reveal a Leishmania immune subversion strategy targeting host cell epigenetic regulation to establish conditions beneficial for parasite survival and open avenues for host-directed, anti-microbial drug discovery.