Signaling through Toll-like receptor 4 and mast cell-dependent innate immunity responses

Signal transduction through Toll-like receptors (TLRs) has been one of the main topics in immunology research in recent years. Because of their signaling particularities based on the homotypic recognition of protein domains in multiple adaptors and selective activation of protein kinases, TLRs have become a paradigm to study ligand recognition coupled to dynamic and highly specific transcriptional and secretory responses in immune cells. Particularly, deleterious effects of Gram-negative bacteria-associated immune reactions has promoted intense research in the field, leading to the description of a number of canonical molecules connecting lipopolysaccharide-induced TLR4 activation with NFκB-dependent transcription. However, the diversity of immune cell phenotypes and the activity of distinct immune receptors in the same cell, strongly suggest that a number of elements in TLR4 signaling cascade, such as novel coreceptors, tyrosine kinases, and molecules regulating the secretion of preformed mediators remain to be described. Recent investigations have placed the mast cells, widely known by their role on allergic responses, as important effectors of innate immunity reactions against Gram-negative bacteria. Their remarkable capacity of cytokine storage, synthesis and release, and the large number of inflammatory reactions controlled by their activation, suggest the existence of new modulators of TLR4 signaling in this particular cell type.