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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.This study provides comprehensive mechanistic insight into helminth-induced immunomodulation, which can be therapeutically exploited to combat various auto-immune disorders.

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 non-classical human monocytes. Primary human monocytes were cultured for 16 h in the presence or absence of TsSP (40 μg/ml) and subsequently analysed by flow cytometry for classical and non-classical monocyte markers like (a and b) CD14 and CD16 as well as (c-e) CCR2 and CX3CR1 on live gated cells. Experiments were performed in triplicate using cells derived from 5 different human donors and the results are presented by FACS plots (a and c) or the mean percentage of positive cells +/− SEM (b, d and e). *p < 0.05 as determined by Students t test
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Fig1: TsSP induce non-classical human monocytes. Primary human monocytes were cultured for 16 h in the presence or absence of TsSP (40 μg/ml) and subsequently analysed by flow cytometry for classical and non-classical monocyte markers like (a and b) CD14 and CD16 as well as (c-e) CCR2 and CX3CR1 on live gated cells. Experiments were performed in triplicate using cells derived from 5 different human donors and the results are presented by FACS plots (a and c) or the mean percentage of positive cells +/− SEM (b, d and e). *p < 0.05 as determined by Students t test

Mentions: To identify the pathways by which T. suis soluble products (TsSP) affect the innate immune system, we first investigated whether TsSP causes changes in the phenotype of human blood monocytes. As shown in Fig. 1a and c, these circulating cells can be divided into two subpopulations; a large population of inflammatory CD14 expressing cells (CD14++CD16−, classical monocytes) with high CCR2 expression, and a small population of anti-inflammatory CD16 expressing cells (CD14dimCD16++, non-classical monocytes and a CD14+CD16+ intermediate population) with high CX3CR1 expression. Interestingly, TsSP treatment of monocytes results in a decreased percentage of classical CD14++CD16− monocytes and an increased percentage of CD14dimCD16++ non-classical monocytes (Fig. 1b). Moreover, TsSP treatment significantly reduces the proportion of CCR2-positive cells in classical monocytes and slightly but not significantly induces the proportion of CX3CR1-positive cells in non-classical monocytes (Fig. 1d, e). These results indicate that TsSP predominantly affect classical monocytes, by inducing a shift from classical to non-classical cells.Fig. 1


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 non-classical human monocytes. Primary human monocytes were cultured for 16 h in the presence or absence of TsSP (40 μg/ml) and subsequently analysed by flow cytometry for classical and non-classical monocyte markers like (a and b) CD14 and CD16 as well as (c-e) CCR2 and CX3CR1 on live gated cells. Experiments were performed in triplicate using cells derived from 5 different human donors and the results are presented by FACS plots (a and c) or the mean percentage of positive cells +/− SEM (b, d and e). *p < 0.05 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

Fig1: TsSP induce non-classical human monocytes. Primary human monocytes were cultured for 16 h in the presence or absence of TsSP (40 μg/ml) and subsequently analysed by flow cytometry for classical and non-classical monocyte markers like (a and b) CD14 and CD16 as well as (c-e) CCR2 and CX3CR1 on live gated cells. Experiments were performed in triplicate using cells derived from 5 different human donors and the results are presented by FACS plots (a and c) or the mean percentage of positive cells +/− SEM (b, d and e). *p < 0.05 as determined by Students t test
Mentions: To identify the pathways by which T. suis soluble products (TsSP) affect the innate immune system, we first investigated whether TsSP causes changes in the phenotype of human blood monocytes. As shown in Fig. 1a and c, these circulating cells can be divided into two subpopulations; a large population of inflammatory CD14 expressing cells (CD14++CD16−, classical monocytes) with high CCR2 expression, and a small population of anti-inflammatory CD16 expressing cells (CD14dimCD16++, non-classical monocytes and a CD14+CD16+ intermediate population) with high CX3CR1 expression. Interestingly, TsSP treatment of monocytes results in a decreased percentage of classical CD14++CD16− monocytes and an increased percentage of CD14dimCD16++ non-classical monocytes (Fig. 1b). Moreover, TsSP treatment significantly reduces the proportion of CCR2-positive cells in classical monocytes and slightly but not significantly induces the proportion of CX3CR1-positive cells in non-classical monocytes (Fig. 1d, e). These results indicate that TsSP predominantly affect classical monocytes, by inducing a shift from classical to non-classical cells.Fig. 1

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.This study provides comprehensive mechanistic insight into helminth-induced immunomodulation, which can be therapeutically exploited to combat various auto-immune disorders.

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