RESUMEN
Recognition of cell death by the innate immune system triggers inflammatory responses. However, how these reactions are regulated is not well understood. Here, we identify the inhibitory C-type lectin receptor Clec12a as a specific receptor for dead cells. Both human and mouse Clec12a could physically sense uric acid crystals (monosodium urate, MSU), which are key danger signals for cell-death-induced immunity. Clec12a inhibited inflammatory responses to MSU in vitro, and Clec12a-deficient mice exhibited hyperinflammatory responses after being challenged with MSU or necrotic cells and after radiation-induced thymocyte killing in vivo. Thus, we identified a negative regulatory MSU receptor that controls noninfectious inflammation in response to cell death that has implications for autoimmunity and inflammatory disease.
Asunto(s)
Muerte Celular , Inflamación/metabolismo , Lectinas Tipo C/metabolismo , Receptores Mitogénicos/metabolismo , Ácido Úrico/metabolismo , Animales , Muerte Celular/genética , Muerte Celular/inmunología , Línea Celular , Inflamación/genética , Inflamación/inmunología , Lectinas Tipo C/genética , Ratones , Ratones Noqueados , Modelos Biológicos , Activación Neutrófila/genética , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptores Mitogénicos/genética , Ácido Úrico/inmunologíaRESUMEN
Members of the PRDM protein family have been shown to play important roles during embryonic development. Previous in vitro and in situ analyses indicated a function of Prdm6 in cells of the vascular system. To reveal physiological functions of Prdm6, we generated conditional Prdm6-deficient mice. Complete deletion of Prdm6 results in embryonic lethality due to cardiovascular defects associated with aberrations in vascular patterning. However, smooth muscle cells could be regularly differentiated from Prdm6-deficient embryonic stem cells and vascular smooth muscle cells were present and proliferated normally in Prdm6-deficient embryos. Conditional deletion of Prdm6 in the smooth muscle cell lineage using a SM22-Cre driver line resulted in perinatal lethality due to hemorrhage in the lungs. We thus identified Prdm6 as a factor that is essential for the physiological control of cardiovascular development.