Hoeksema Marten A, Laan Lisa C, Postma Juliette J, Cummings Richard D, de Winther Menno P J, Dijkstra Christine D, van Die Irma, Kooij Gijs
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands;
Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and.
FASEB J. 2016 Aug;30(8):2826-36. doi: 10.1096/fj.201600343R. Epub 2016 Apr 19.
Helminths have strong immunoregulatory properties that may be exploited in treatment of chronic immune disorders, such as multiple sclerosis and inflammatory bowel disease. Essential players in the pathogenesis of these diseases are proinflammatory macrophages. We present evidence that helminths modulate the function and phenotype of these innate immune cells. We found that soluble products derived from the Trichuris suis (TsSP) significantly affect the differentiation of monocytes into macrophages and their subsequent polarization. TsSPs reduce the expression and production of inflammatory cytokines, including IL-6 and TNF, in human proinflammatory M1 macrophages. TsSPs induce a concomitant anti-inflammatory M2 signature, with increased IL-10 production. Furthermore, they suppress CHIT activity and enhance secretion of matrix metalloproteinase 9. Short-term triggering of monocytes with TsSPs early during monocyte-to-macrophage differentiation imprinted these phenotypic alterations, suggesting long-lasting epigenetic changes. The TsSP-induced effects in M1 macrophages were completely reversed by inhibiting histone deacetylases, which corresponded with decreased histone acetylation at the TNF and IL6 promoters. These results demonstrate that TsSPs have a potent and sustained immunomodulatory effect on human macrophage differentiation and polarization through epigenetic remodeling and provide new insights into the mechanisms by which helminths modulate human immune responses.-Hoeksema, M. A., Laan, L. C., Postma, J. J., Cummings, R. D., de Winther, M. P. J., Dijkstra, C. D., van Die, I., Kooij, G. Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling.
蠕虫具有强大的免疫调节特性，可用于治疗慢性免疫疾病，如多发性硬化症和炎症性肠病。这些疾病发病机制中的关键因素是促炎性巨噬细胞。我们提供的证据表明，蠕虫可调节这些固有免疫细胞的功能和表型。我们发现，猪鞭虫的可溶性产物（TsSP）显著影响单核细胞向巨噬细胞的分化及其随后的极化。TsSP可降低人促炎性M1巨噬细胞中炎性细胞因子（包括IL-6和TNF）的表达和产生。TsSP可诱导伴随的抗炎性M2特征，同时增加IL-10的产生。此外，它们可抑制几丁质酶活性并增强基质金属蛋白酶9的分泌。在单核细胞向巨噬细胞分化的早期，用TsSP对单核细胞进行短期刺激可印记这些表型改变，这表明存在持久的表观遗传变化。通过抑制组蛋白脱乙酰酶可完全逆转TsSP对M1巨噬细胞的诱导作用，这与TNF和IL6启动子处组蛋白乙酰化减少相对应。这些结果表明 TsSP 通过表观遗传重塑对人巨噬细胞分化和极化具有强大而持久的免疫调节作用，并为蠕虫调节人免疫反应的机制提供了新见解。-霍克塞马，M. A.，拉恩，L. C.，波斯特马，J. J.，卡明斯，R. D.，德温特，M. P. J.，迪克斯塔，C. D.，范迪，I.，库伊，G. 单核细胞向巨噬细胞分化过程中用猪鞭虫可溶性产物治疗可通过表观遗传重塑减少炎症反应
