Defining the consequences of CD14 engagement and NFAT activation in innate immune cells: from molecular mechanisms to a preclinical model

DCs sense the presence of pathogens through germline-encoded PRRs, which recognize molecular patterns expressed by various microorganisms and endogenous stimuli. Following activation with LPS, DCs sequentially acquire the ability to produce soluble and cell surface molecules critical for the initiation and control of innate and then adaptive immune responses. The production of most of these factors is regulated by the activation of TLR4-MD2 pathway. Nevertheless, we have recently described that following LPS exposure different NFAT isoforms are also activated. The initiation of the pathway that leads to nuclear NFAT translocation is totally dependent on CD14 that, through the activation of src family kinases and PLCγ2, leads to Ca2+ mobilization and calcineurin activation. Nuclear NFAT translocation is required for IL-2 production and apoptotic cell death of terminally differentiated DCs. In the present work, we analyzed the role of CD14-NFAT pathway in a preclinical model of skin edema formation and its implications in antigen delivery. In addition, we investigated the Ca2+ entry process in LPS-stimulated DCs, defining the molecular mechanism downstream CD14 activation that leads to Ca2+ mobilization.