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Curtailment of Toll-like receptor signalling and cytokine production in dendritic cells by secreted products of Heligmosomoides polygyrus

ABSTRACT: Dendritic cells (DCs) are the professional antigen-presenting cells responsible for recognition of pathogens and induction of appropriate adaptive immune responses. Many successful pathogens have evolved to release molecular products that can manipulate DC responses to dampen immunity. Here, we report that the excretory/secretory (ES) products of the intestinal helminth Heligmosomoides polygyrus bakeri profoundly repress the ability of murine bone marrow derived DCs to respond to canonical stimuli delivered through Toll-like Receptors (TLRs), e.g. LPS. To further investigate the effect of HES on GMDC activation in response to LPS, we compared gene-expression profiles of LPS-treated and LPS+HES-treated cells. It was noted that HES broadly reduced the transcript levels of activation markers such as costimulatory molecules (e.g. CD40 and CD83) and pro-inflammatory cytokines (e.g. IL-12p35, LT-α and IL-23p19), and even some TLRs (e.g. TLR1 and TLR6). On the other hand, HES-treatment increased the expression of type-2 markers such as IL-33 and arginase 1, and transcripts of genes involved in cellular metabolism (e.g. HIF1A, Hmox, and Txnip).

ORGANISM(S): Mus musculus

PROVIDER: GSE313792 | GEO | 2026/07/04

REPOSITORIES: GEO

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			Action	DRS
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	GSE313792_ControlGeneProfile_190914.txt.gz	Txt
	GSE313792_ControlProbeProfile_190914.txt.gz	Txt
	GSE313792_SampleGeneProfile_190914.txt.gz	Txt
	GSE313792_SampleProbeProfile_190914.txt.gz	Txt

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Project description:Dendritic cells (DCs) are key initiators of the adaptive immunity, and upon recognition of pathogens are able to skew T cell differentiation to elicit appropriate responses. DCs possess this extraordinary capacity to discern external signals using receptors that recognize pathogen-associated molecular patterns. These can be glycan-binding receptors that recognize carbohydrate structures on pathogens or pathogen-associated patterns that additionally bind receptors, such as Toll-like receptors (TLRs). This study explores the early signaling events in DCs upon binding of α2-3 sialic acid (α2-3sia) that are recognized by Immune inhibitory Sialic acid binding immunoglobulin type lectins. α2-3sias are commonly found on bacteria, e.g. Group B Streptococcus, but can also be expressed by tumor cells. We investigated whether α2-3sia conjugated to a dendrimeric core alters DC signaling properties. Through phosphoproteomic analysis, we found differential signaling profiles in DCs after α2-3sia binding alone or in combination with LPS/TLR4 co-stimulation. α2-3sia was able to modulate the TLR4 signaling cascade, resulting in 109 altered phosphoproteins. These phosphoproteins were annotated to seven biological processes, including the regulation of the IL-12 cytokine pathway. Secretion of IL-10, the inhibitory regulator of IL-12 production, by DCs was found upregulated after overnight stimulation with the α2-3sia dendrimer. Analysis of kinase activity revealed altered signatures in the JAK-STAT signaling pathway. PhosphoSTAT3 (Ser727) and phosphoSTAT5A (Ser780), involved in the regulation of the IL-12 pathway, were both downregulated. Flow cytometric quantification indeed revealed de- phosphorylation over time upon stimulation with α2-3sia, but no α2-6sia. Inhibition of both STAT3 and -5A in moDCs resulted in a similar cytokine secretion profile as α-3sia triggered DCs. Conclusively, this study revealed a specific alteration of the JAK-STAT pathway in DCs upon simultaneous α2-3sia and LPS stimulation, altering the IL10:IL-12 cytokine secretion profile associated with reduction of inflammation. Targeted control of the STAT phosphorylation status is therefore an interesting lead for the abrogation of immune escape that bacteria or tumors impose on the host.

Project description:The IL-33/ST2 pathway is important as part of the type 2 immune response against helminth infections. Mast cells express the highest levels of the IL-33 receptor subunit ST2 of any immune cell, and mast cells can mediate type 2 immune inflammation, however the role of IL-33-driven mast cell responses in helminth infection is poorly understood. We sought to determine the role of mast cell ST2 expression during Heligmosomoides polygyrus bakeri (Hpb) infection by generating mast cell conditional ST2 knockout (MCPT5Cre x ST2f/f ,cKO) mice. These mice have normal frequencies of mast cells at steady state, but show specific and strong (albeit incomplete) knockdown of ST2 expression on mast cells. On Hpb infection, faecal egg and adult worm burden were similar between cKO and littermate controls, as were mast cell degranulation markers, serum IgE and goblet cell hyperplasia. Therefore, we conclude that mast cell ST2 does not play a dominant role in Hpb infection. To further investigate the immune response to infection in cKO and littermate controls, transcriptomic and proteomic changes were assessed in duodenal tissues in infected versus naïve mice in cKO and control mice. Minimal transcriptomic and proteomic changes were seen between genotypes, whereas substantial changes were seen between naïve and infected mice, regardless of genotype. Hpb infection induced local increases at the transcript and protein level for mast cell proteases (MCPT1 and MCPT2), resistin-like molecules (RELMα and RELMβ), and markers such as the phospholipase PLA2G4C and the pore-forming protein gasdermin C. Bulk proteomic analysis was also searched against the Hpb genome to identify Hpb proteins present in the duodenal tissues. A list of 60 Hpb proteins of interest were identified in infected duodenal samples, of which 18 contain a signal peptide and are present in the excretory/secretory products of Hpb (HES) (likely secretory products including immunomodulatory proteins); 28 proteins are present in HES but do not contain a signal peptide (likely excretory products); and 14 proteins are not present in HES (likely proteins present in the remnants of Hpb within the duodenum). This work thus provides datasets for changes in the mouse intestine due to Hpb infection, at both the transcript and protein level, as well as a dataset of Hpb proteins detectable in the mouse duodenum at day 14 of infection.

Project description:The IL-33/ST2 pathway is important as part of the type 2 immune response against helminth infections. Mast cells express the highest levels of the IL-33 receptor subunit ST2 of any immune cell, and mast cells can mediate type 2 immune inflammation, however the role of IL-33-driven mast cell responses in helminth infection is poorly understood. We sought to determine the role of mast cell ST2 expression during Heligmosomoides polygyrus bakeri (Hpb) infection by generating mast cell conditional ST2 knockout (MCPT5Cre x ST2f/f, cKO) mice. These mice have normal frequencies of mast cells at steady state, but show specific and strong (albeit incomplete) knockdown of ST2 expression on mast cells. On Hpb infection, faecal egg and adult worm burden were similar between cKO and littermate controls, as were mast cell degranulation markers, serum IgE and goblet cell hyperplasia. Therefore, we conclude that mast cell ST2 does not play a dominant role in Hpb infection. To further investigate the immune response to infection in cKO and littermate controls, transcriptomic and proteomic changes were assessed in duodenal tissues in infected versus naïve mice in cKO and control mice. Minimal transcriptomic and proteomic changes were seen between genotypes, whereas substantial changes were seen between naïve and infected mice, regardless of genotype. Hpb infection induced local increases at the transcript and protein level for mast cell proteases (MCPT1 and MCPT2), resistin-like molecules (RELMα and RELMβ), and markers such as the phospholipase PLA2G4C and the pore-forming protein gasdermin C. Bulk proteomic analysis was also searched against the Hpb genome to identify Hpb proteins present in the duodenal tissues. A list of 60 Hpb proteins of interest were identified in infected duodenal samples, of which 18 contain a signal peptide and are present in the excretory/secretory products of Hpb (HES) (likely secretory products including immunomodulatory proteins); 28 proteins are present in HES but do not contain a signal peptide (likely excretory products); and 14 proteins are not present in HES (likely proteins present in the remnants of Hpb within the duodenum). This work thus provides datasets for changes in the mouse intestine due to Hpb infection, at both the transcript and protein level, as well as a dataset of Hpb proteins detectable in the mouse duodenum at day 14 of infection.

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Curtailment of Toll-like receptor signalling and cytokine production in dendritic cells by secreted products of Heligmosomoides polygyrus

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