IL-10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF-κB p50 member in Trypanosoma congolense infection-resistant C57BL/6 mice
IL-10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF-κB p50 member in Trypanosoma congolense infection-resistant C57BL/6 mice
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DOI：
10.1002/eji.201041307
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发表时间：
2011-11-01
影响因子：
5.4
通讯作者：
Beschin, Alain
中科院分区：
文献类型：
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作者：
Bosschaerts, Tom;Morias, Yannick;Beschin, Alain
消灭寄生虫和控制与感染相关的致病性之间的平衡对于抵抗非洲锥虫病至关重要。通过产生肿瘤坏死因子和一氧化氮，具有经典激活状态(M1)的CD11b(+)髓系细胞有助于在耐药的C57BL/6小鼠中控制实验性锥虫感染的原虫血症。然而，在这些小鼠中，需要IL-10来调节M1相关的炎症，避免组织/肝脏损伤，并确保延长生存时间。为了分析IL-10在感染弓形虫的C57BL/6小鼠中的抗炎作用机制，我们用一种阻断IL-10受体的抗体表明，IL-10损害了产生肿瘤坏死因子/诱导型一氧化氮合酶的CD11b(+)Ly6C(+)细胞在肝脏中的聚集和M1激活。利用感染的IL-10(FLOX/FLOX)LysM-Cre(+/+)小鼠，我们发现髓系细胞来源的IL-10在产生肿瘤坏死因子的水平上特异性地限制了CD11b(+)Ly6C(+)细胞的M1激活。此外，在感染IL-10(FLOX/FLOX)LysM-Cre(+/+)小鼠中，较高的肿瘤坏死因子的产生与CD11b(+)M1细胞中核转录因子-kappa B p50亚单位的核积累减少有关。此外，在感染p50(-/-)小鼠中，CD11b(+)Ly6C(+)细胞产生的肿瘤坏死因子增加，肝脏损伤增加。这些数据表明，p50的优先核积聚代表了M1型CD11b(+)髓系细胞中依赖IL-10的抗炎机制，该机制调节了耐药C57BL/6小鼠感染弓形虫时致病肿瘤坏死因子的产生。
A balance between parasite elimination and control of infection-associated pathogenicity is crucial for resistance to African trypanosomiasis. By producing TNF and NO, CD11b(+) myeloid cells with a classical activation status (M1) contribute to parasitemia control in experimental Trypanosoma congolense infection in resistant C57BL/6 mice. However, in these mice, IL-10 is required to regulate M1-associated inflammation, avoiding tissue/liver damage and ensuring prolonged survival. In an effort to dissect the mechanisms behind the anti-inflammatory activity of IL-10 in T. congolense-infected C57BL/6 mice, we show, using an antibody blocking the IL-10 receptor, that IL-10 impairs the accumulation and M1 activation of TNF/iNOS-producing CD11b(+)Ly6C(+) cells in the liver. Using infected IL-10(flox/flox)LysM-Cre(+/+) mice, we show that myeloid cell-derived IL-10 limits M1 activation of CD11b(+)Ly6C(+) cells specifically at the level of TNF production. Moreover, higher production of TNF in infected IL-10(flox/flox)LysM-Cre(+/+) mice is associated with reduced nuclear accumulation of the NF-kappa B p50 subunit in CD11b(+) M1 cells. Furthermore, in infected p50(-/-) mice, TNF production by CD11b(+)Ly6C(+) cells and liver injury increases. These data suggest that preferential nuclear accumulation of p50 represents an IL-10-dependent anti-inflammatory mechanism in M1-type CD11b(+) myeloid cells that regulates the production of pathogenic TNF during T. congolense infection in resistant C57BL/6 mice.