Severe Listeria monocytogenes infection induces development of monocytes with distinct phenotypic and functional features.
Severe Listeria monocytogenes infection induces development of monocytes with distinct phenotypic and functional features.
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DOI：
10.4049/jimmunol.1000486
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发表时间：
2010-08-15
期刊：
影响因子：
--
通讯作者：
Leenen PJ
中科院分区：
文献类型：
--
作者：
Drevets DA;Schawang JE;Mandava VK;Dillon MJ;Leenen PJ
单核细胞在感染兼性细胞内单核增生李斯特菌时发挥不同的作用。它们是宿主防御中必不可少的杀菌细胞，但也可能成为将细菌运送到大脑中的特洛伊木马。为了解释这些不同的作用，我们研究了稳态和致死性和亚致死性单核细胞增生乳杆菌感染期间产生的骨髓（BM）单核细胞。在稳定状态和亚致死感染后72小时，Ly-6ChighCD11b+ BM单核细胞表达大量M-CSFR/CD115。然而，随着细菌数量的增加，感染导致CD115的逐渐丢失，并强烈降低编码CD115的c-fms mRNA的表达。相反，调控分子分析显示，在相同条件下，非信号IL-1RII CD121b从头表达。在致死性感染期间，循环中的Ly-6ChighCD11b+单核细胞也获得了CD115neg/lowCD121bhigh表型。与亚致死感染的细胞相比，这些BM单核细胞表现出更大程度和/或更早的细胞因子信号传导1和3抑制因子以及il - 1r相关激酶- m的上调，尽管表面TLR4表达水平相似，但lps诱导的IL-6产生减少。未感染或亚致死性感染小鼠的骨髓单核细胞在体外结合并内化很少的单核增生乳杆菌。然而，在致死性感染期间，这两种功能在单核细胞发育中都显著增加。尽管如此，这些细胞不产生活性氧中间体，这表明它们无法杀死单核增生乳杆菌。总之，这些数据表明，致死性和亚致死性细菌的全身性感染对发育中的骨髓单核细胞有不同的影响。这导致不同的表型和功能特性与特洛伊木马一致，而不是杀菌效应细胞。
Monocytes perform diverse roles during infection with the facultative intracellular bacterium Listeria monocytogenes. They are essential as bactericidal cells in host defense but can also become Trojan horses transporting bacteria into the brain. To explain these contrasting roles, we characterized bone marrow (BM) monocytes in steady state and generated during lethal and sublethal L. monocytogenes infection. Ly-6ChighCD11b+ BM monocytes expressed high amounts of M-CSFR/CD115 in steady state and 72 h following sublethal infection. However, infection with increasing numbers of bacteria resulted in progressive loss of CD115 and strongly decreased CD115-encoding c-fms mRNA expression. Conversely, analysis of regulatory molecules showed de novo expression of the nonsignaling IL-1RII, CD121b, under the same conditions. Ly-6ChighCD11b+ monocytes in circulation also acquired a CD115neg/lowCD121bhigh phenotype during lethal infection. These BM monocytes showed upregulation of suppressor of cytokine signaling 1 and 3 and IL-1R–associated kinase-M to a greater extent and/or earlier compared with cells from sublethal infection and showed decreased LPS-induced IL-6 production despite similar levels of surface TLR4 expression. BM monocytes from uninfected or sublethally infected mice bound and internalized very few L. monocytogenes in vitro. However, both functions were significantly increased in monocytes developing during lethal infection. Nonetheless, these cells did not produce reactive oxygen intermediates, suggesting an inability to kill L. monocytogenes. Together, these data show that systemic infections with lethal and sublethal amounts of bacteria differentially shape developing BM monocytes. This results in distinct phenotypic and functional properties consistent with being Trojan horses rather than bactericidal effector cells.
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