IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
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DOI：
10.4049/jimmunol.1003349
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发表时间：
2011-05-01
影响因子：
4.4
通讯作者：
Ronnblom, Lars
中科院分区：
文献类型：
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作者：
Hagberg, Niklas;Berggren, Olof;Ronnblom, Lars
几种全身性自身免疫性疾病表现出明显的干扰素特征。这是由于浆细胞样树突状细胞(PDC)持续产生干扰素-α，并由含有核酸的免疫复合体(IC)激活。最近发现，由抗RNP自身抗体和U1小核糖核蛋白颗粒组成的含RNA IC(RNA-IC)刺激的pDC产生的干扰素-α可被单核细胞抑制，但可被NK细胞增强。单核细胞的抑制作用是由肿瘤坏死因子-α、前列腺素E(2)和活性氧介导的，但NK细胞介导的干扰素-α产生增加的机制尚不清楚。在这项研究中，我们研究了NK细胞增加pDC产生RNA-IC诱导的干扰素-α的机制。此外，对系统性红斑狼疮(SLE)患者的NK细胞促进干扰素-α产生的能力进行了评估。我们发现，CD56(Dim)NK细胞在RNA-IC激活后可使干扰素-α的产生增加1000倍，而CD56(明亮)的NK细胞需要IL-12和IL-18的共同刺激才能促进干扰素-α的产生。NK细胞通过RNA-IC介导的Fc-γRIIIA活化产生MIP-1α、MIP-1β、RANTES、干扰素-γ和肿瘤坏死因子-α。NK细胞通过分泌MIP-1β和LFA介导的细胞-细胞接触促进pDC产生干扰素-α。此外，SLE患者的NK细胞对RNA-IC诱导的干扰素-α产生的促进能力降低，外源性IL-12和IL-18可使其恢复。因此，不同的分子机制可以介导依赖NK细胞的RNA-IC刺激的pDC产生干扰素-α的增加，我们的研究表明，在干扰素-α驱动的自身免疫性疾病(如SLE)中，应研究以NK-PDC轴为治疗靶点的可能性。免疫学杂志，2011,186：5085-5094。
Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-alpha production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-alpha production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-alpha, PGE(2), and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-alpha production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC-induced IFN-alpha production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-alpha production. We found that CD56(dim) NK cells could increase IFN-alpha production > 1000-fold after RNA-IC activation, whereas CD56(bright) NK cells required costimulation by IL-12 and IL-18 to promote IFN-alpha production. NK cells produced MIP-1 alpha, MIP-1 beta, RANTES, IFN-gamma, and TNF-alpha via RNA-IC-mediated Fc gamma RIIIA activation. The IFN-alpha production in pDCs was promoted by NK cells via MIP-1 beta secretion and LFA-mediated cell-cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC-induced IFN-alpha production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-alpha production by RNA-IC-stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK-pDC axis in IFN-alpha-driven autoimmune diseases such as SLE should be investigated. The Journal of Immunology, 2011, 186: 5085-5094.