Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells
Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells
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DOI：
10.4049/jimmunol.1001952
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发表时间：
2011-06-15
影响因子：
4.4
通讯作者：
Hancock, Robert E. W.
中科院分区：
文献类型：
--
作者：
Pena, Olga M.;Pistolic, Jelena;Hancock, Robert E. W.
已知单核细胞（MNC）（如单核细胞和巨噬细胞）的经典（M1）和交替（M2）极化响应于微环境内的挑战（如遇到病原体）而发生。LPS，也称为内毒素，是炎症和M1极化的有效诱导剂。LPS还可以在MNC中产生称为内毒素耐受性的效应，其定义为在初始暴露于该刺激后细胞对LPS活化的响应能力降低。使用涉及微阵列和高级生物信息学分析的PBMC、单核细胞和单核细胞衍生的巨噬细胞中的系统生物学方法，我们确定内毒素耐受期间的基因反应与M2极化期间发现的基因反应相似，其特征在于对关键M2 MNC功能的发展至关重要的基因和蛋白质表达，包括促炎介质的产生减少，参与吞噬作用的基因表达，以及组织重塑。此外，不同的金属硫蛋白基因亚型的表达，已知其在氧化应激的控制和免疫调节中的作用，也被发现一致上调内毒素耐受。这些结果表明，在初始炎症刺激后，人MNC经历M2极化，可能是为了控制过度炎症并愈合受影响的组织。免疫学杂志，2011，186：7243-7254。
Classical (M1) and alternative (M2) polarization of mononuclear cells (MNCs) such as monocyte and macrophages is known to occur in response to challenges within a microenvironment, like the encounter of a pathogen. LPS, also known as endotoxin, is a potent inducer of inflammation and M1 polarization. LPS can also generate an effect in MNCs known as endotoxin tolerance, defined as the reduced capacity of a cell to respond to LPS activation after an initial exposure to this stimulus. Using systems biology approaches in PBMCs, monocytes, and monocyte-derived macrophages involving microarrays and advanced bioinformatic analysis, we determined that gene responses during endotoxin tolerance were similar to those found during M2 polarization, featuring gene and protein expression critical for the development of key M2 MNC functions, including reduced production of proinflammatory mediators, expression of genes involved in phagocytosis, as well as tissue remodeling. Moreover, expression of different metallothionein gene isoforms, known for their role in the control of oxidative stress and in immunomodulation, were also found to be consistently upregulated during endotoxin tolerance. These results demonstrate that after an initial inflammatory stimulus, human MNCs undergo an M2 polarization probably to control hyperinflammation and heal the affected tissue. The Journal of Immunology, 2011, 186: 7243-7254.