Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1-deficient mice
Aberrant macrophage and neutrophil population dynamics and impaired Th1 response to Listeria monocytogenes in colony-stimulating factor 1-deficient mice
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DOI：
10.1128/iai.69.3.1795-1807.2001
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发表时间：
2001-03-01
影响因子：
3.1
通讯作者：
Pollard, JW
中科院分区：
文献类型：
--
作者：
Guleria, I;Pollard, JW
单核细胞增生李斯特菌是一种兼性胞内菌，已被广泛用于研究固有免疫应答。巨噬细胞既是这种细菌的宿主，也是抵御它的主要防线。利用单核吞噬细胞生长因子集落刺激因子1（CSF - 1）基因纯合缺失突变（Csf1(op)）的小鼠，我们已经证明，CSF - 1调控的巨噬细胞对于抵御李斯特菌感染至关重要。在缺乏CSF - 1的情况下，由于缺乏巨噬细胞趋化因子趋化因子MCP - 1的合成，单核细胞不会被募集到感染部位。此外，也没有白细胞介素 - 10（IL - 10）合成的爆发，而这种爆发已被证明会导致中性粒细胞从感染部位流出。因此，中性粒细胞没有被巨噬细胞取代，出现了大量充满中性粒细胞的微脓肿，随后组织遭到破坏，小鼠死亡。与野生型小鼠相比，在CSF - 1基因缺失纯合小鼠中，γ干扰素（IFN - γ）的合成也非常低，导致巨噬细胞活化降低。然而，在这种细菌负荷下，诱导IFN - γ的细胞因子IL - 12和IL - 18的浓度在这些突变小鼠中是相似的。相比之下，IL - 6的浓度显著降低。给Csf1(op)/Csf1(op)小鼠施用IL - 6比单独用IFN - γ治疗更显著地增加了IFN - γ的合成，并在更大程度上降低了细菌负荷。这些数据表明，IL - 6在CSF - 1调控的巨噬细胞对单核细胞增生李斯特菌的应答中起着核心作用。
Listeria monocytogenes, a facultative intracellular bacterium, has been used extensively to study innate immune responses. Macrophages act as hosts for this bacterium as well as a major defense against it, Using mice homozygous for a null mutation (Csf1(op)) in the gene for the mononuclear phagocytic growth factor colony-stimulating factor 1 (CSF-1), we have demonstrated that CSF-l-regulated macrophages were essential to defend against a listerial infection. In the absence of CSF-1, monocytes were not recruited to the sites of infection due to the lack of synthesis of the macrophage chemoattractant chemokine MCP-1. In addition, there was no burst of interleukin-10 (IL-10) synthesis that has been shown to result in the egress of neutrophils from sites of infection. Consequently, neutrophils were not replaced by macrophages, and numerous neutrophil-filled microabscesses developed, followed by tissue destruction and death of the mice. In the CSF-1 nullizygous mice compared to wild-type mice, there was also a very low synthesis of gamma interferon (IFN-gamma), resulting in reduced macrophage activation. However, the concentrations of the IFN-gamma -inducing cytokines IL-12 and IL-18 at this bacterial load were similar in these mutant mice. In contrast, IL-6 concentrations were dramatically reduced. Administration of IL-6 to Csf1(op)/Csf1(op) mice significantly increased the synthesis of IFN-gamma and reduced the bacterial burden to a greater extent than treatment with IFN-gamma alone. These data indicate that IL-6 occupies a central role in the CSF-l-regulated macrophage response to L. monocytogenes.