1. Dectin-1/2-induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses.
- Author
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Kaisar MMM, Ritter M, Del Fresno C, Jónasdóttir HS, van der Ham AJ, Pelgrom LR, Schramm G, Layland LE, Sancho D, Prazeres da Costa C, Giera M, Yazdanbakhsh M, and Everts B
- Subjects
- Animals, Antigens, Helminth immunology, Antigens, Helminth pharmacology, Autocrine Communication, Cell Differentiation, Cyclooxygenase 1 genetics, Cyclooxygenase 1 immunology, Cyclooxygenase 2 genetics, Cyclooxygenase 2 immunology, Dendritic Cells drug effects, Dendritic Cells parasitology, Dinoprostone metabolism, Enterotoxins pharmacology, Gene Expression Regulation, Humans, Lectins, C-Type deficiency, Lectins, C-Type genetics, MAP Kinase Signaling System, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Membrane Proteins genetics, Membrane Proteins immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, OX40 Ligand, Phospholipases A2 genetics, Phospholipases A2 immunology, Primary Cell Culture, Reactive Oxygen Species immunology, Reactive Oxygen Species metabolism, Schistosomiasis mansoni genetics, Schistosomiasis mansoni parasitology, Schistosomiasis mansoni pathology, Syk Kinase genetics, Syk Kinase immunology, Th2 Cells drug effects, Th2 Cells parasitology, Tumor Necrosis Factors genetics, Tumor Necrosis Factors immunology, Dendritic Cells immunology, Dinoprostone immunology, Lectins, C-Type immunology, Schistosoma mansoni immunology, Schistosomiasis mansoni immunology, Th2 Cells immunology
- Abstract
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 Schistosoma mansoni, 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 S. mansoni 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.
- Published
- 2018
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