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Polysaccharides from edible mushrooms possess important immunomodulating effects on immune cells including monocytes and macrophages. Macrophages activated by LPS/IFNγ are polarized toward inflammatory macrophages, whereas the anti-inflammatory properties of alternative activated macrophages play an important regulatory role in the innate immune system. We here show that the Pleurotus citrinopileatus mushroom polysaccharide (PCPS) can modulate the monocyte-to-macrophage differentiation early at the monocyte stage. Using both human THP-1 monocytic cells as well as human peripheral monocytes, we showed that PCPS inhibits the secreted levels of the pro-inflammatory cytokines TNF and IL-6, after stimulation of macrophages derived from PCPS-treated monocytes, with IFNγ + LPS. In addition, the glucan induced a tendency to increase the secreted levels of the anti-inflammatory cytokine IL-10, enhanced the expression levels of CCL2 and CCL8 mRNAs, and inhibited expression of CCR2 mRNA in the IFNγ/LPS activated macrophages. Interestingly, these data suggest that PCPS can induce a long-lasting anti-inflammatory effect in monocytes. Treatment of monocytes with laminarin and antibodies against Dectin-1 and TLR2 during PCPS treatment affected the glucan-modulated macrophage differentiation. In summary, the results of this study indicate that the glucan directs the differentiation of monocytes toward a macrophage cell population with reduced pro-inflammatory capacity via Dectin-1 and TLR2., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (© FASEB.)

Introduction: The inverse correlation between prevalence of auto-immune disorders like the chronic neuro-inflammatory disease multiple sclerosis (MS) and the occurrence of helminth (worm) infections, suggests that the helminth-trained immune system is protective against auto-immunity. As monocytes are regarded as crucial players in the pathogenesis of auto-immune diseases, we explored the hypothesis that these innate effector cells are prime targets for helminths to exert their immunomodulatory effects., Results: Here we show that soluble products of the porcine nematode Trichuris suis (TsSP) are potent in changing the phenotype and function of human monocytes by skewing classical monocytes into anti-inflammatory patrolling cells, which exhibit reduced trans-endothelial migration capacity in an in vitro model of the blood-brain barrier. Mechanistically, we identified the mannose receptor as the TsSP-interacting monocyte receptor and we revealed that specific downstream signalling occurs via protein kinase C (PKC), and in particular PKCδ., Conclusion: This study provides comprehensive mechanistic insight into helminth-induced immunomodulation, which can be therapeutically exploited to combat various auto-immune disorders.

Mistire Wolde, 1, 2 Lisa C Laan, 3 Girmay Medhin, 1 Endalemaw Gadissa, 4 Nega Berhe, 1, 5 Aster Tsegaye 2 1Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Medical Laboratory Sciences, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia; 3Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands; 4Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia; 5Oslo University Hospital-Ulleval, Centre for Imported and Tropical Diseases, Oslo, NorwayCorrespondence: Mistire WoldeAklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, EthiopiaEmail mistire08@gmail.comIntroduction: Epidemiological and animal studies indicate that helminth infections have positive effects due to their potential to protect against autoimmune diseases. Here, we aim to assess the effect of S. mansoni infection on immune modulation of human monocytes and their potential protection against autoimmune disease development both in vivo and in vitro.Materials and Methods: Monocytes were isolated from helminth-infected Ethiopians (MHIE), and from Dutch healthy volunteers (MHV). The MHV were stimulated in vitro with S. mansoni soluble egg antigens (SEA) or soluble worm antigens (SWA). In addition, phenotypical changes were studied directly, as well as after culturing for 6 days in the presence of human serum to obtain macrophages. Q-PCR, flow cytometry, multiplex bead immunoassay, and live-cell imaging were employed during analysis.Results: MHIE showed elevated transcripts of SOCS-1 and TNF-α compared to MHV. Similarly, MHV that were stimulated with SEA demonstrated enhanced levels of SOCS-1, IL-10, and IL-12 mRNA, compared to control MHV. Remarkably, the SEA-treated monocytes showed a much higher motility than control monocytes, a hallmark of a patrolling phenotype. Furthermore, in vitro cultured macrophages that were stimulated by SEA exhibited enhanced mRNA levels of SOCS-1, IL-10, TNF-α, IL-12 and TGF-β, compared to control macrophages.Conclusion: Macrophages from MHIE as well as SEA-treated MHV show an intermediate activation phenotype with both pro-inflammatory and anti-inflammatory characteristics in vitro. The observed pro-inflammatory properties might reflect a recent response of the cells due to contact with a pathogen, whereas the anti-inflammatory properties might contribute to helminth-induced protection against inflammatory diseases. Large-scale study is recommended to consolidate the findings of the present study.Keywords: Schistosoma mansoni, immune modulation, monocytes, macrophages