Signal Transduction Pathways Activated by Innate Immunity in Mast Cells: Translating Sensing of Changes into Specific Responses

Mast cells (MCs) constitute an essential cell lineage that participates in innate and adaptive immune responses and whose phenotype and function are influenced by tissue-specific conditions. Their mechanisms of activation in type I hypersensitivity reactions have been the subject of multiple studies, but the signaling pathways behind their activation by innate immunity stimuli are not so well described. Here, we review the recent evidence regarding the main molecular elements and signaling pathways connecting the innate immune receptors and hypoxic microenvironment to cytokine synthesis and the secretion of soluble or exosome-contained mediators in this cell type. When known, the positive and negative control mechanisms of those pathways are presented, together with their possible implications for the understanding of mast cell-driven chronic inflammation. Finally, we discuss the relevance of the knowledge about signaling in this cell type in the recognition of MCs as central elements on innate immunity, whose remarkable plasticity converts them in sensors of micro-environmental discontinuities and controllers of tissue homeostasis

TLR4 Receptor Induces 2-AG–Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

International audienceMast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo