RESUMEN
Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non-histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies.
Asunto(s)
Dermatitis Atópica/inmunología , Neuroinmunomodulación , Prurito/inmunología , Enfermedad Crónica , Dermatitis Atópica/complicaciones , Humanos , Queratinocitos/inmunología , Prurito/tratamiento farmacológico , Prurito/etiologíaRESUMEN
Natural killer (NK) cell cytotoxicity is determined by a balance of positive and negative signals. Negative signals are transmitted by NK inhibitory receptors (killer immunoglobulin-like receptors, KIR) at the site of membrane apposition between an NK cell and a target cell, where inhibitory receptors become clustered with class I MHC ligands in an organized structure known as an inhibitory NK immune synapse. Immune synapse formation in NK cells is poorly understood. Because signaling by NK inhibitory receptors could be involved in this process, the human NK tumor line YTS was transfected with signal-competent and signal-incompetent KIR2DL1. The latter were generated by truncating the KIR2DL1 cytoplasmic tail or by introducing mutations in the immunoreceptor tyrosine-based inhibition motifs. The KIR2DL1 mutants retained their ability to cluster class I MHC ligands on NK cell interaction with appropriate target cells. Therefore, receptor-ligand clustering at the inhibitory NK immune synapse occurs independently of KIR2DL1 signal transduction. However, parallel examination of NK cell membrane lipid rafts revealed that KIR2DL1 signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity. Moreover, raft polarization was inhibited by reagents that disrupt microtubules and actin filaments, whereas synapse formation was not. Thus, NK lipid raft polarization and inhibitory NK immune synapse formation occur by fundamentally distinct mechanisms.
