Limits...
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 interacts with the MR on human monocytes. The effect of blocking antibodies for the mannose receptor (MR, CD206) or its isotype control (both 10 μg/ml) on (a) the TsSP-induced patrolling phenotype or (b) transendothelial migration capacity was tested and subsequently quantified. Experiments were performed in triplicate using cells derived from 8 (a) or 5 (b) different human donors and the results are presented as the mean +/− SEM. ** or ##p < 0.01, ***p < 0.001 as determined by ANOVA and Students t test
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: TsSP interacts with the MR on human monocytes. The effect of blocking antibodies for the mannose receptor (MR, CD206) or its isotype control (both 10 μg/ml) on (a) the TsSP-induced patrolling phenotype or (b) transendothelial migration capacity was tested and subsequently quantified. Experiments were performed in triplicate using cells derived from 8 (a) or 5 (b) different human donors and the results are presented as the mean +/− SEM. ** or ##p < 0.01, ***p < 0.001 as determined by ANOVA and Students t test

Mentions: The contribution of periodate-sensitive TsSP moieties in the modulation of monocyte function suggests that glycans on TsSP may be recognized by glycan-binding receptors such as C-type lectins (CLRs), leading to an altered monocyte behaviour. We have recently shown that DCs can bind to TsSP via the mannose receptor (MR, CD206) and that TsSP are strongly bound by ConA, suggesting the presence of oligo-mannose-type glycans on TsSP [9]. Next to the MR, the TsSP glycans may also be recognized by other monocytic CLRs with mannose recognizing potential like Dectin-2 [31]. To evaluate this possibility, we first analyzed the expression of such CLRs on monocytes, which show that both the MR and Dectin-2 are expressed and that MR expression is induced upon TsSP treatment (Additional file 2). Next, we evaluated the involvement of the MR and Dectin-2 in modulating monocyte behaviour. Interestingly, treatment of monocytes with TsSP in the presence of a MR blocking antibody significantly inhibited the TsSP-induced patrolling behaviour of monocytes (Fig. 5a) and rescued the TsSP-induced reduction in monocyte trans-endothelial migration (Fig. 5b). In contrast, blocking of Dectin-2 did not affect monocyte patrolling behaviour and monocyte transendothelial migration (Additional file 3), suggesting that TsSP predominantly exerts its effect on human monocytes via the MR.Fig. 5


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 interacts with the MR on human monocytes. The effect of blocking antibodies for the mannose receptor (MR, CD206) or its isotype control (both 10 μg/ml) on (a) the TsSP-induced patrolling phenotype or (b) transendothelial migration capacity was tested and subsequently quantified. Experiments were performed in triplicate using cells derived from 8 (a) or 5 (b) different human donors and the results are presented as the mean +/− SEM. ** or ##p < 0.01, ***p < 0.001 as determined by ANOVA and Students t test
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: TsSP interacts with the MR on human monocytes. The effect of blocking antibodies for the mannose receptor (MR, CD206) or its isotype control (both 10 μg/ml) on (a) the TsSP-induced patrolling phenotype or (b) transendothelial migration capacity was tested and subsequently quantified. Experiments were performed in triplicate using cells derived from 8 (a) or 5 (b) different human donors and the results are presented as the mean +/− SEM. ** or ##p < 0.01, ***p < 0.001 as determined by ANOVA and Students t test
Mentions: The contribution of periodate-sensitive TsSP moieties in the modulation of monocyte function suggests that glycans on TsSP may be recognized by glycan-binding receptors such as C-type lectins (CLRs), leading to an altered monocyte behaviour. We have recently shown that DCs can bind to TsSP via the mannose receptor (MR, CD206) and that TsSP are strongly bound by ConA, suggesting the presence of oligo-mannose-type glycans on TsSP [9]. Next to the MR, the TsSP glycans may also be recognized by other monocytic CLRs with mannose recognizing potential like Dectin-2 [31]. To evaluate this possibility, we first analyzed the expression of such CLRs on monocytes, which show that both the MR and Dectin-2 are expressed and that MR expression is induced upon TsSP treatment (Additional file 2). Next, we evaluated the involvement of the MR and Dectin-2 in modulating monocyte behaviour. Interestingly, treatment of monocytes with TsSP in the presence of a MR blocking antibody significantly inhibited the TsSP-induced patrolling behaviour of monocytes (Fig. 5a) and rescued the TsSP-induced reduction in monocyte trans-endothelial migration (Fig. 5b). In contrast, blocking of Dectin-2 did not affect monocyte patrolling behaviour and monocyte transendothelial migration (Additional file 3), suggesting that TsSP predominantly exerts its effect on human monocytes via the MR.Fig. 5

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