title: The helminth Trichuris suis suppresses TLR4-induced inflammatory responses in human macrophages.
abstract: Recent clinical trials in patients with inflammatory diseases like multiple sclerosis (MS) or inflammatory bowel disease (IBD) have shown the beneficial effects of probiotic helminth administration, although the underlying mechanism of action remains largely unknown. Potential cellular targets may include innate immune cells that propagate inflammation in these diseases, like pro-inflammatory macrophages. We here investigated the effects of the helminth Trichuris suis soluble products (SPs) on the phenotype and function of human inflammatory (granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated) macrophages. Interestingly, we here show that T. suis SPs potently skew inflammatory macrophages into a more anti-inflammatory state in a Toll-like receptor 4 (TLR4)-dependent manner, and less effects are seen when stimulating macrophages with TLR2 or -3 ligands. Gene microarray analysis of GM-CSF-differentiated macrophages further revealed that many TLR4-induced inflammatory mediators, including interleukin (IL)-12B, CCL1 and CXCL9, are downregulated by T. suis SPs. In particular, we observed a strong reduction in the expression and function of P2RX7, a purinergic receptor involved in macrophage inflammation, leading to reduced IL-1β secretion. In conclusion, we show that T. suis SPs suppress a broad range of inflammatory pathways in GM-CSF-differentiated macrophages in a TLR4-dependent manner, thereby providing enhanced mechanistic insight into the therapeutic potential of this helminth for patients with inflammatory diseases.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: M K
authors.initials: MK
authors.lastname: Ottow
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Klaver
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: T C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: P D
authors.initials: PD
authors.lastname: Heijnen
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L C
authors.initials: LC
authors.lastname: Laan
authors.affiliation: Section for Parasitology, Health and Development, Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Kringel
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: D Y S
authors.initials: DY
authors.lastname: Vogel
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: C D
authors.initials: CD
authors.lastname: Dijkstra
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kooij
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: van Die
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054402:Chemokine CCL1 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015801:Helminth Proteins / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014258:Trichuris / Q000737:chemistry / Q000276:immunology*
chemical_list: D054402:Chemokine CCL1; D054370:Chemokine CXCL9; D015801:Helminth Proteins; D053762:Interleukin-12 Subunit p40; D058486:Receptors, Purinergic P2X7; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor