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Trichuris suis induces human non-classical patrolling monocytes via the mannose receptor and PKC: implications for multiple sclerosis.

Kooij G, Braster R, Koning JJ, Laan LC, van Vliet SJ, Los T, Eveleens AM, van der Pol SM, Förster-Waldl E, Boztug K, Belot A, Szilagyi K, van den Berg TK, van Buul JD, van Egmond M, de Vries HE, Cummings RD, Dijkstra CD, van Die I - Acta Neuropathol Commun (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. G.kooij@vumc.nl.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

TsSP induce pro- and anti-inflammatory responses in human monocytes. Primary human monocytes were cultured for 2 or 16 h in the presence or absence of TsSP (40 μg/ml) after which various pro- and anti-inflammatory mediators were determined by (a-e) real-time quantitative PCR (qRT-PCR) and presented as relative expression (FI: fold induction) compared to GAPDH, by (f-i) enzyme-linked immunosorbent assay in cell supernatants (16 h) or by (j) dihydrorhodamine (DHR) flow cytometric assay to determine ROS (16 h). Experiments were performed in triplicate using cells derived from 5 different human donors and results are presented as the mean +/− SEM. **p < 0.01, ***p < 0.001 as determined by Students t test
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Fig2: TsSP induce pro- and anti-inflammatory responses in human monocytes. Primary human monocytes were cultured for 2 or 16 h in the presence or absence of TsSP (40 μg/ml) after which various pro- and anti-inflammatory mediators were determined by (a-e) real-time quantitative PCR (qRT-PCR) and presented as relative expression (FI: fold induction) compared to GAPDH, by (f-i) enzyme-linked immunosorbent assay in cell supernatants (16 h) or by (j) dihydrorhodamine (DHR) flow cytometric assay to determine ROS (16 h). Experiments were performed in triplicate using cells derived from 5 different human donors and results are presented as the mean +/− SEM. **p < 0.01, ***p < 0.001 as determined by Students t test

Mentions: To further investigate these phenotypic alterations, we analysed the effects of TsSP on gene expression levels of various anti-inflammatory markers including SOCS1, IL-10 and TGFβ, as well as pro-inflammatory cytokines like TNF-α and IL-6 in purified monocytes. As shown in Fig. 2a-e, TsSP treatment significantly induces gene expression of both pro- and anti-inflammatory markers. Next, the levels of secreted IL-10, TGFβ, TNF-α and IL-6 were determined, as well as the production of reactive oxygen species (ROS), a typical marker of inflammatory monocytes [16]. In line with the transcriptional results (Fig. 2a-e), TsSP significantly enhances the secretion (Fig. 2f-i) and production (Fig. 2j) of these pro- and anti-inflammatory mediators. Of note, the induction of anti-inflammatory genes occurs predominantly at later time points (16 h) compared to the induction of pro-inflammatory genes (2 h), thereby distinguishing the acute inflammatory response to the pathogen from the apparent secondary anti-inflammatory response. Together, these results suggest that TsSP potently affect the classical monocyte population, by lowering their CCR2 expression. In turn, this may lead to a shift into non-classical cells and concomitantly elicit a differential cytokine response.Fig. 2


Trichuris suis induces human non-classical patrolling monocytes via the mannose receptor and PKC: implications for multiple sclerosis.

Kooij G, Braster R, Koning JJ, Laan LC, van Vliet SJ, Los T, Eveleens AM, van der Pol SM, Förster-Waldl E, Boztug K, Belot A, Szilagyi K, van den Berg TK, van Buul JD, van Egmond M, de Vries HE, Cummings RD, Dijkstra CD, van Die I - Acta Neuropathol Commun (2015)

TsSP induce pro- and anti-inflammatory responses in human monocytes. Primary human monocytes were cultured for 2 or 16 h in the presence or absence of TsSP (40 μg/ml) after which various pro- and anti-inflammatory mediators were determined by (a-e) real-time quantitative PCR (qRT-PCR) and presented as relative expression (FI: fold induction) compared to GAPDH, by (f-i) enzyme-linked immunosorbent assay in cell supernatants (16 h) or by (j) dihydrorhodamine (DHR) flow cytometric assay to determine ROS (16 h). Experiments were performed in triplicate using cells derived from 5 different human donors and results are presented as the mean +/− SEM. **p < 0.01, ***p < 0.001 as determined by Students t test
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4513676&req=5

Fig2: TsSP induce pro- and anti-inflammatory responses in human monocytes. Primary human monocytes were cultured for 2 or 16 h in the presence or absence of TsSP (40 μg/ml) after which various pro- and anti-inflammatory mediators were determined by (a-e) real-time quantitative PCR (qRT-PCR) and presented as relative expression (FI: fold induction) compared to GAPDH, by (f-i) enzyme-linked immunosorbent assay in cell supernatants (16 h) or by (j) dihydrorhodamine (DHR) flow cytometric assay to determine ROS (16 h). Experiments were performed in triplicate using cells derived from 5 different human donors and results are presented as the mean +/− SEM. **p < 0.01, ***p < 0.001 as determined by Students t test
Mentions: To further investigate these phenotypic alterations, we analysed the effects of TsSP on gene expression levels of various anti-inflammatory markers including SOCS1, IL-10 and TGFβ, as well as pro-inflammatory cytokines like TNF-α and IL-6 in purified monocytes. As shown in Fig. 2a-e, TsSP treatment significantly induces gene expression of both pro- and anti-inflammatory markers. Next, the levels of secreted IL-10, TGFβ, TNF-α and IL-6 were determined, as well as the production of reactive oxygen species (ROS), a typical marker of inflammatory monocytes [16]. In line with the transcriptional results (Fig. 2a-e), TsSP significantly enhances the secretion (Fig. 2f-i) and production (Fig. 2j) of these pro- and anti-inflammatory mediators. Of note, the induction of anti-inflammatory genes occurs predominantly at later time points (16 h) compared to the induction of pro-inflammatory genes (2 h), thereby distinguishing the acute inflammatory response to the pathogen from the apparent secondary anti-inflammatory response. Together, these results suggest that TsSP potently affect the classical monocyte population, by lowering their CCR2 expression. In turn, this may lead to a shift into non-classical cells and concomitantly elicit a differential cytokine response.Fig. 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. G.kooij@vumc.nl.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus