MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity.
MIR337-3p Enhances Mycobacterial Pathogenicity Involving TLR4/MYD88 and STAT3 Signals, Impairing VDR Antimicrobial Response and Fast-Acting Immunity.
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DOI：
10.3389/fimmu.2021.739219
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发表时间：
2021
影响因子：
7.3
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Liang S;Huang G;Wu T;Peng Y;Liu X;Ji X;Sha W;Wang F;Shen L;Shen H
活性形式的维生素D（VitD）可增强人类对结核分枝杆菌（Mtb）感染的先天免疫。我们前期的研究表明MIR 337 - 3 p在结核病患者的淋巴细胞中高表达。在这里，我们确定了MIR 337 - 3 p通过抑制维生素D依赖性抗微生物反应途径来调节速效抗结核免疫的机制。虽然在细胞模型和小鼠中分枝杆菌感染诱导了高水平的MIR 337 - 3 p表达，但TB患者在CD 14+单核细胞/巨噬细胞、先天性样Vγ2+ T细胞和含有自然杀伤（NK）/先天性淋巴细胞的CD 8+淋巴细胞中表现出显著增加的MIR 337 - 3 p。MIR 337 - 3 p促进分枝杆菌在宿主靶细胞（巨噬细胞和肺上皮细胞）中的进入/感染和复制/生长。这种MIR 337 - 3 p增强的致病性与MIR 337 - 3 p抑制细胞色素P450，家族27，亚家族B，多肽1（CYP 27 B1）/β-防御素4（DEFB 4A）/凯萨林菌素抗菌肽CAMP途径的维生素D依赖性抗菌反应相一致。令人惊讶的是，单个MIR 337 - 3 p物质可以特异性靶向Toll样受体4（TLR 4）和信号转导子和转录激活子3（STAT 3）3′-非翻译区（UTR），以抑制TLR 4/MYD 88和STAT 3信号，并削弱抑制巨噬细胞中维生素D依赖性抗微生物途径的两种信号中的任一种。同时，表达高水平MIR 337 - 3 p的人外周血单核细胞（PBMC）表现出先天性细胞群针对细胞内分枝杆菌感染的快速作用细胞免疫的能力降低。此外，小鼠分枝杆菌感染后Mir 337 - 3 p的更高表达与肺中更大的集落形成单位（CFU）计数一致，甚至与感染动物的死亡一致，而感染小鼠的Mir 337 - 3 p抑制剂治疗降低了Mir 337 - 3 p水平并逆转了Mir 337 - 3 p介导的CFU计数增加。因此，TB驱动的单一MIR 337 - 3 p物质可以特异性靶向/削弱TLR 4/MYD 88和STAT 3激活信号，抑制维生素D依赖性抗微生物应答和速效抗TB免疫，导致致病性增强。
Active form of vitamin D (VitD) enhances human innate immunity against Mycobacterium tuberculosis (Mtb) infection. Our previous studies showed that MIR337-3p was highly expressed in lymphocytes of tuberculosis (TB) patients. Here, we identified the mechanism of MIR337-3p in the regulation of fast-acting anti-TB immunity by inhibiting VitD-dependent antimicrobial response pathways. While high-level MIR337-3p expression was induced by mycobacterial infection in cellular models and mice, TB patients exhibited significantly increased MIR337-3p in CD14+ monocytes/macrophages, innate-like Vγ2+ T cells, and CD8+ lymphocytes containing natural killer (NK)/innate lymphoid cells. MIR337-3p promoted the mycobacterial entry/infection and replication/growth in host target cells: macrophages and lung epithelial cells. Such MIR337-3p-enhanced pathogenicity coincided with the MIR337-3p depression of VitD-dependent antimicrobial response of cytochrome P450, family 27, subfamily b, polypeptide 1 (CYP27B1)/Beta-defensin 4 (DEFB4A)/ cathelicidin antimicrobial peptide CAMP pathways. Surprisingly, single MIR337-3p species could specifically target both the Toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) 3′-untranslated regions (UTRs) to depress the TLR4/MYD88 and STAT3 signals and impair either of the two signals inhibiting the VitD-dependent antimicrobial pathways in macrophages. Concurrently, human peripheral blood mononuclear cells (PBMCs) expressing high-level MIR337-3p exhibited a reduced ability of innate cell populations to mount fast-acting cellular immunity against intracellular mycobacterial infection. Furthermore, a higher expression of Mir337-3p after mycobacterial infection of mice coincided with much greater colony-forming unit (CFU) counts in lungs and even the death of infected animals, whereas Mir337-3p inhibitor treatment of infected mice reduced Mir337-3p levels and reversed Mir337-3p-mediated increases in CFU counts. Thus, TB-driven single MIR337-3p species could specifically target/impair both TLR4/MYD88 and STAT3 activation signals, inhibiting VitD-dependent antimicrobial response and fast-acting anti-TB immunity, leading to enhanced pathogenicity.