Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses
Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses
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DOI：
10.1128/jvi.00912-13
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Slobedman, Barry
中科院分区：
文献类型：
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作者：
Avdic, Selmir;Cao, John Z.;Slobedman, Barry
几种人类巨细胞病毒（HCMV）基因编码的产物以一种可能增强病毒发病机制的方式调节细胞功能。这包括UL111A，它编码人类白细胞介素-10 （hIL-10）的同源物。根据接收到的信号，单核细胞和巨噬细胞分化为经典激活（M1促炎）或选择性激活（M2抗炎）亚群。向M2亚群偏斜的极化可能通过限制对感染的促炎反应而有利于病毒，因此我们确定了hcmv编码的病毒IL-10是否影响单核细胞极化。重组病毒IL-10蛋白将CD14（+）单核细胞极化为具有M2c表型的抗炎M2亚群，证实了CD163和CD14的高表达以及主要组织相容性复合体（MHC） II类的抑制。值得注意的是，在生产性HCMV感染的情况下，受感染细胞产生的病毒IL-10将未感染的单核细胞极化为M2c表型。我们还评估了病毒IL-10对血红素加氧酶1 （HO-1）的影响，这是一种与炎症反应抑制有关的酶。病毒IL-10对单核细胞的极化导致HO-1的上调，HO-1功能的抑制导致病毒IL-10抑制肿瘤坏死因子α (tnf - α)和IL-1 β的能力丧失，暗示HO-1参与了病毒IL-10诱导的M2c单核细胞对促炎因子的抑制。此外，单核细胞与病毒IL-10极化的功能后果是激活CD4(+) T细胞的能力下降。这项研究确定了病毒IL-10在驱动M2c极化中的新作用，这可能通过限制感染部位的促炎和CD4(+) T细胞反应来限制病毒清除。
Several human cytomegalovirus (HCMV) genes encode products that modulate cellular functions in a manner likely to enhance viral pathogenesis. This includes UL111A, which encodes homologs of human interleukin-10 (hIL-10). Depending upon signals received, monocytes and macrophages become polarized to either classically activated (M1 proinflammatory) or alternatively activated (M2 anti-inflammatory) subsets. Skewing of polarization toward an M2 subset may benefit the virus by limiting the proinflammatory responses to infection, and so we determined whether HCMV-encoded viral IL-10 influenced monocyte polarization. Recombinant viral IL-10 protein polarized CD14(+) monocytes toward an anti-inflammatory M2 subset with an M2c phenotype, as demonstrated by high expression of CD163 and CD14 and suppression of major histocompatibility complex (MHC) class II. Significantly, in the context of productive HCMV infection, viral IL-10 produced by infected cells polarized uninfected monocytes toward an M2c phenotype. We also assessed the impact of viral IL-10 on heme oxygenase 1 (HO-1), which is an enzyme linked with suppression of inflammatory responses. Polarization of monocytes by viral IL-10 resulted in upregulation of HO-1, and inhibition of HO-1 function resulted in a loss of capacity of viral IL-10 to suppress tumor necrosis factor alpha (TNF-alpha) and IL-1 beta, implicating HO-1 in viral IL-10-induced suppression of proinflammatory cytokines by M2c monocytes. In addition, a functional consequence of monocytes polarized with viral IL-10 was a decreased capacity to activate CD4(+) T cells. This study identifies a novel role for viral IL-10 in driving M2c polarization, which may limit virus clearance by restricting proinflammatory and CD4(+) T cell responses at sites of infection.