Baranzini Nicolò, Pedrini Edoardo, Girardello Rossana, Tettamanti Gianluca, de Eguileor Magda, Taramelli Roberto, Acquati Francesco, Grimaldi Annalisa
Department of Biotechnology and Life Sciences, University of Insubria, Via J. H. Dunant 3, 21100, Varese, Italy.
Cell Tissue Res. 2017 May;368(2):337-351. doi: 10.1007/s00441-016-2557-9. Epub 2017 Jan 9.
In recent years, several studies have demonstrated that the RNASET2 gene is involved in the control of tumorigenicity in ovarian cancer cells. Furthermore, a role in establishing a functional cross-talk between cancer cells and the surrounding tumor microenvironment has been unveiled for this gene, based on its ability to act as an inducer of the innate immune response. Although several studies have reported on the molecular features of RNASET2, the details on the mechanisms by which this evolutionarily conserved ribonuclease regulates the immune system are still poorly defined. In the effort to clarify this aspect, we report here the effect of recombinant human RNASET2 injection and its role in regulating the innate immune response after bacterial challenge in an invertebrate model, the medicinal leech. We found that recombinant RNASET2 injection induces fibroplasias, connective tissue remodeling and the recruitment of numerous infiltrating cells expressing the specific macrophage markers CD68 and HmAIF1. The RNASET2-mediated chemotactic activity for macrophages has been further confirmed by using a consolidated experimental approach based on injection of the Matrigel biomatrice (MG) supplemented with recombinant RNASET2 in the leech body wall. One week after injection, a large number of CD68 and HmAIF-1 macrophages massively infiltrated MG sponges. Finally, in leeches challenged with lipopolysaccharides (LPS) or with the environmental bacteria pathogen Micrococcus nishinomiyaensis, numerous macrophages migrating to the site of inoculation expressed high levels of endogenous RNASET2. Taken together, these results suggest that RNASET2 is likely involved in the initial phase of the inflammatory response in leeches.
近年来，多项研究表明RNASET2基因参与了卵巢癌细胞致瘤性的调控。此外，基于其作为先天性免疫反应诱导剂的能力，该基因在癌细胞与周围肿瘤微环境之间建立功能性相互作用中所起的作用也已被揭示。尽管已有多项研究报道了RNASET2的分子特征，但关于这种进化保守的核糖核酸酶调节免疫系统的机制细节仍不清楚。为了阐明这一方面，我们在此报告重组人RNASET2注射的效果及其在无脊椎动物模型医用蛭中细菌攻击后调节先天性免疫反应中的作用。我们发现，注射重组RNASET2会诱导成纤维细胞形成、结缔组织重塑以及大量表达特异性巨噬细胞标志物CD68和HmAIF1的浸润细胞的募集。通过在蛭体壁注射补充了重组RNASET2的基质胶（MG）这一成熟的实验方法，进一步证实了RNASET2介导的对巨噬细胞的趋化活性。注射一周后，大量CD68和HmAIF-1巨噬细胞大量浸润MG海绵。最后，在用脂多糖（LPS）或环境细菌病原体西宫微球菌攻击的蛭中，大量迁移到接种部位的巨噬细胞表达高水平的内源性RNASET2。综上所述，这些结果表明RNASET2可能参与了蛭炎症反应的初始阶段。
