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Basophil activation through TLR2 and TLR4 signaling pathways

1 INSERM U1016, Institut Cochin, Paris, France
2 CNRS-UMR 8104, Paris, France
3 Université Paris Descartes, 75014 Paris, France
4 CNRS-UMR 8147, Hôpital Necker, 75015 Paris, France
5 Labex inflamex, Paris, France

Basophils are effector cells that respond to protease allergens and parasites, thus contributing to allergic inflammation and Th2 differentiation. However, the molecular interactions through which pathogens promote activation as well as recruitment of these cells to sites of inflammation remain poorly understood. We found that administration of extracts from Nippostrongylus brasiliensis induced both basophil recruitment into blood and liver in vivo and IL-4 and histamine production by purified bone marrow-derived basophils in vitro. Starting from this finding, we set out to identify putative pathogen-derived molecules for their capacity to activate murine basophils, using a basophil population differentiated and expanded from bone marrow cells cultured with IL-3 and sorted as a CD49b+ c-kit subset. Among a number of Toll-like receptor (TLR) agonists tested, we found that the lipopeptide Pam2CSK4 and lipopolysaccharide (LPS) activate basophils in terms of IL-4, IL-6 and histamine production through TLR2 and TLR4, respectively. By contrast, TLR3 or TLR7 agonists had no such effect. We further identified nitric oxide (NO) as key mediator for LPS stimulation and established that in vivo administration of LPS led to basophil recruitment into the liver. Our results reveal the important contribution of MyD88 and NO signaling to antigen recognition through TLR2 and TLR4 pathways leading to activation, degranulation and release of immunoregulatory mediators.
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