Notch-1 Signaling Modulates Macrophage Polarization and Immune Defense againstMycobacterium avium paratuberculosisInfection in Inflammatory Diseases
Notch-1 Signaling Modulates Macrophage Polarization and Immune Defense againstMycobacterium avium paratuberculosisInfection in Inflammatory Diseases
复制标题
Notch-1信号通路调节炎症性疾病中巨噬细胞极化和抗副结核分枝杆菌感染的免疫防御
DOI：
10.3390/microorganisms8071006
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发表时间：
2020-07-01
期刊：
影响因子：
4.5
通讯作者：
Naser, Saleh A.
中科院分区：
文献类型：
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作者：
Keewan, Esra'a;Naser, Saleh A.
尽管对Notch信号参与炎症的研究非常广泛，但其在自身免疫性疾病巨噬细胞反应中的具体作用以及对细菌感染（如鸟副结核分枝杆菌（MAP））的防御机制仍不清楚。在这项研究中，我们研究了Notch-1信号在MAP感染过程中巨噬细胞反应中的分子作用。特别是，我们在体外测量了MAP对Notch-1信号的影响，以及对白细胞介素(IL)-6和骨髓细胞白血病序列-1 （MCL-1）的下游影响，以及随之而来的细胞凋亡、MAP活力和巨噬细胞极化。总体而言，数据显示map感染的巨噬细胞中Notch-1、IL-6和MCL-1显著上调，同时这些感染细胞的凋亡减少和促炎反应升高。相反，用γ -分泌酶抑制剂（DAPT）阻断Notch信号会降低MAP的存活和负担，增加细胞凋亡，减少促炎反应。特别是，用DAPT治疗感染的巨噬细胞使巨噬细胞极化向M2抗炎表型反应转变。这项研究的结果清楚地证明了Notch信号在感染期间巨噬细胞反应中的关键作用。我们得出结论，巨噬细胞中的MAP感染激活Notch-1信号并下游影响IL-6，从而劫持MCL-1依赖性的凋亡抑制，导致其慢性持续和进一步的炎症。这项研究支持Notch-1信号作为对抗自身免疫性疾病（如克罗恩病和类风湿性关节炎）感染的治疗靶点。
Despite the extensive research on Notch signaling involvement in inflammation, its specific role in macrophage response in autoimmune disease and defense mechanisms against bacterial infection, such asMycobacterium avium paratuberculosis(MAP), remains unknown. In this study, we investigated the molecular role of Notch-1 signaling in the macrophage response during MAP infection. In particular, we measured the in vitro effect of MAP on Notch-1 signaling and downstream influence on interleukin (IL)-6 and myeloid cell leukemia sequence-1 (MCL-1) and consequent cellular apoptosis, MAP viability, and macrophage polarization. Overall, the data show significant upregulation in Notch-1, IL-6, and MCL-1 in MAP-infected macrophages, parallel with a decrease in apoptosis and elevated pro-inflammatory response in these infected cells. On the contrary, blocking Notch signaling with gamma-secretase inhibitor (DAPT) decreased MAP survival and burden, increased apoptosis, and diminished the pro-inflammatory response. In particular, the treatment of infected macrophages with DAPT shifted macrophage polarization toward M2 anti-inflammatory phenotypic response. The outcome of this study clearly demonstrates the critical role of Notch signaling in macrophage response during infection. We conclude that MAP infection in macrophages activates Notch-1 signaling and downstream influence on IL-6 which hijack MCL-1 dependent inhibition of apoptosis leading to its chronic persistence, and further inflammation. This study supports Notch-1 signaling as a therapeutic target to combat infection in autoimmune diseases such as Crohn's disease and Rheumatoid Arthritis.