Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses

Soluble egg antigens of the parasitic helminth Schistosoma mansoni (S. mansoni egg antigen [SEA]) induce strong Th2 responses both in vitro and in vivo. However, the specific molecules that prime the development of Th2 responses have not been identified. We report that omega-1, a glycoprotein which is secreted from S. mansoni eggs and present in SEA, is capable of conditioning human monocyte-derived dendritic cells in vitro to drive T helper 2 (Th2) polarization with similar characteristics as whole SEA. Furthermore, using IL-4 dual reporter mice, we show that both natural and recombinant omega-1 alone are sufficient to generate Th2 responses in vivo, even in the absence of IL-4R signaling. Finally, omega-1–depleted SEA displays an impaired capacity for Th2 priming in vitro, but not in vivo, suggesting the existence of additional factors within SEA that can compensate for the omega-1–mediated effects. Collectively, we identify omega-1, a single component of SEA, as a potent inducer of Th2 responses

C-Reactive protein promotes inflammation through FcγR-Induced glycolytic reprogramming of human macrophages

C-reactive protein (CRP) is an acute-phase protein produced in high quantities by the liver in response to infection and during chronic inflammatory disorders. Although CRP is known to facilitate the clearance of cell debris and bacteria by phagocytic cells, the role of CRP in additional immunological functions is less clear. This study shows that complexed CRP (phosphocholine [PC]:CRP) (formed by binding of CRP to PC moieties), but not soluble CRP, synergized with specific TLRs to posttranscriptionally amplify TNF, IL-1β, and IL-23 production by human inflammatory macrophages. We identified FcγRI and IIa as the main receptors responsible for initiating PC:CRP-induced inflammation. In addition, we identified the underlying mechanism, which depended on signaling through kinases Syk, PI3K, and AKT2, as well as glycolytic reprogramming. These data indicate that in humans, CRP is not only a marker but also a driver of inflammation by human macrophages. Therefore, although providing host defense against bacteria, PC:CRP-induced inflammation may also exacerbate pathology in the context of disorders such as atherosclerosis

IgG Subclasses Shape Cytokine Responses by Human Myeloid Immune Cells through Differential Metabolic Reprogramming

IgG Abs are crucial for various immune functions, including neutralization, phagocytosis, and Ab-dependent cellular cytotoxicity. In this study, we identified another function of IgG by showing that IgG immune complexes elicit distinct cytokine profiles by human myeloid immune cells, which are dependent on FcgR activation by the different IgG subclasses. Using monoclonal IgG subclasses with identical Ag specificity, our data demonstrate that the production of Th17-inducing cytokines, such as TNF, IL-1b, and IL-23, is particularly dependent on IgG2, whereas type I IFN responses are controlled by IgG3, and IgG1 is able to regulate both. In addition, we identified that subclass-specific cytokine production is orchestrated at the posttranscriptional level through distinct glycolytic reprogramming of human myeloid immune cells. Combined, these data identify that IgG subclasses provide pathogen- and cell type-specific immunity through differential metabolic reprogramming by FcgRs. These findings may be relevant for future design of Ab-related therapies in the context of infectious diseases, chronic inflammation, and cancer

Differences in Innate Cytokine Responses between European and African Children

<div><p>Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerisation domain-like receptors (NLRs) were compared between Dutch (European), semi-urban and rural Gabonese (African) children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF) and the anti-inflammatory/regulatory interleukin-10 (IL-10) cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gabonese children had a lower pro-inflammatory response to poly(I:C) (TLR3 ligand), but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand), Pam3 (TLR2/1 ligand) and LPS (TLR4 ligand) compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.</p></div

Ligands used in the study, their receptors and adapters.

<p>PRR, pattern-recognition receptor. TLR, toll-like receptor. NLR, NOD-like receptor. NOD, nucleotide-binding oligomerisation domain-containing protein 1. SR, scavenger receptor. CLR, C-type lectin receptor. MR, mannose receptor. DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin. TRIF, TIR-domain-containing adapter-inducing interferon-β. MyD88, myeloid differentiation primary response gene 88.</p

Degree of interaction between TLR and non-TLR ligands.

<p>A) Degree of interaction for TNF production upon stimulation with poly(I:C), FSL-1, Pam3 or LPS combined with iE-DAP. This was calculated for e.g. poly(I:C) and iE-DAP by: (TNF^{poly(I:C)+iE-DAP} − TNF^medium)<b><i>/</i></b>((TNF^poly(I:C) − TNF^medium) + (TNF^iE-DAP − TNF^medium)). B) Degree of interaction for IL-10 production for combinations with iE-DAP. C) Degree of interaction for TNF production for combinations with mannan. D) Degree of interaction for IL-10 production for combinations with mannan.</p

Whole blood cytokine responses to TLR ligands.

<p>A) TNF responses to poly(I:C), FLS-1, Pam3 and LPS in European children (the Netherlands), and semi-urban and rural African children (Gabon). B) IL-10 responses to TLR stimulation. C) Pro/anti-inflammatory ratio as calculated by TNF/IL-10 ratio. *p<0.05, **p<0.01, ***p<0.001.</p

Degree of interaction between TLR and non-TLR ligands in Dutch children.

<p>The degree of interaction between two ligands was calculated for <i>e.g.</i> poly(I:C) and iE-DAP by: (TNF^{poly(I:C)+iE-DAP} − TNF^medium)/((TNF^poly(I:C) − TNF^medium) + (TNF^iE-DAP − TNF^medium)). Values above 1 are regarded as synergy (+), and above 2 as strong synergy (++). Values below 1 are regarded as inhibition (−). Shown are statistically significant differences (<i>p</i><0.05) according to the Wilcoxon signed rank test, when comparing the response to combined stimulation with the sum of separate stimulation (after background subtraction). See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095241#pone.0095241.s003" target="_blank">Supplementary figure 3</a> for details.</p

Dectin-1/2–induced autocrine PGE₂ signaling licenses dendritic cells to prime Th2 responses

<div><p>The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from <i>Schistosoma mansoni</i>, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE₂), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE₂ synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A₂ (cPLA₂), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2^−/−, and to a lesser extent Dectin-1^−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following <i>S</i>. <i>mansoni</i> infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE₂-OX40L through which Th2 immune responses are induced.</p></div