Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice
Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice
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DOI：
10.1016/j.imlet.2016.11.012
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Saito, Kuniaki
中科院分区：
文献类型：
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作者：
Kubo, Hisako;Hoshi, Masato;Saito, Kuniaki
脑心肌炎病毒(EMCV)在小鼠体内的感染是一种已建立的病毒性心肌炎模型。以前，我们已经证明了吲哚胺2，3-双加氧酶(IDO)，一种L-色氨酸-犬尿氨酸途径(KP)的酶，影响急性病毒性心肌炎。然而，KP代谢物在EMCV感染中的作用尚不清楚。犬尿氨酸3-单加氧酶(KMO)是细胞内代谢犬尿氨酸为3-羟基犬尿氨酸的关键调节酶之一。因此，我们通过比较KMO-/-小鼠和KMO+/+小鼠来研究KMO在急性病毒感染中的作用。KMO缺乏可抑制EMCV感染后的死亡率。与KMO+/+小鼠相比，KMO-/-小鼠的浸润性细胞数和F4/80(+)细胞数受到抑制。KMO-/-小鼠血清KP代谢物水平显著升高，EMCV感染后KMO表达的诱导与其抑制EMCV对死亡率的影响有关。此外，KMO-/-小鼠在感染后第2天对CCL2、CCL3和CCL4以及感染后第4天对CXCL1表现出明显的抑制作用。这些结果表明，增加的KP代谢物减少了趋化因子的产生，从而抑制了EMCV感染中KMO基因敲除后的死亡率。因此，KP代谢产物可能为治疗急性病毒性心肌炎提供一种有效的策略。(C)2016年欧洲免疫学会联合会。爱思唯尔出版，版权所有。
Infection of the encephalomyocarditis virus (EMCV) in mice is an established model for viral myocarditis. Previously, we have demonstrated that indoleamine 2,3-dioxygenase (IDO), an L-tryptophan - kynurenine pathway (KP) enzyme, affects acute viral myocarditis. However, the roles of KP metabolites in EMCV infection remain unclear. Kynurenine 3-monooxygenase (KMO) is one of the key regulatory enzymes, which metabolizes kynurenine to 3-hydroxykynurenine in the KP. Therefore, we examined the role of KMO in acute viral infection by comparing between KMO-/- mice and KMO+/+ mice. KMO deficiency resulted in suppressed mortality after EMCV infection. The number of infiltrating cells and F4/80(+) cells in KMO-/- mice was suppressed compared with those in KMO+/+ mice. KMO-/- mice showed significantly increased levels of serum KP metabolites, and induction of KMO expression upon EMCV infection was involved in its effect on mortality through EMCV suppression. Furthermore, KMO-/- mice showed significantly suppression of CCL2, CCL3 and CCL4 on day 2 and CXCL1 on day 4 after infection. These results suggest that increased KP metabolites reduced chemokine production, resulting in suppressed mortality upon KMO knockdown in EMCV infection. KP metabolites may thus provide an effective strategy for treating acute viral myocarditis. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.