RESUMO
Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRß signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.
Assuntos
Neoplasias Encefálicas/imunologia , Pontos de Checagem do Ciclo Celular , Glioblastoma/imunologia , Células Matadoras Naturais/imunologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Neoplasias Encefálicas/patologia , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Feminino , Glioblastoma/patologia , Humanos , Imunidade Inata , Interferon gama/metabolismo , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tactile information is perceived by a heterogeneous population of specialized neurons. Neurotrophin receptors (the receptor tyrosine kinases, Trks) mark the major classes of these sensory neurons: TrkA is expressed in neurons that sense temperature and noxious stimuli, and TrkC is expressed in proprioceptive neurons that sense body position. Neurotrophin signaling through these receptors is required for cell survival. To test whether neurotrophins have an instructive role in sensory specification, we expressed rat TrkC from the TrkA (also known as Ntrk1) locus in mice. The surviving presumptive TrkA-expressing neurons adopted a proprioceptive phenotype, indicating that neurotrophin signaling can specify sensory neuron subtypes.
Assuntos
Diferenciação Celular/fisiologia , Gânglios Espinais/fisiologia , Neurônios/fisiologia , Receptor trkA/genética , Receptor trkC/biossíntese , Animais , Southern Blotting , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Fatores de Crescimento Neural , Neurônios/citologia , Fenótipo , Propriocepção/fisiologia , Ratos , Receptor trkC/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologiaRESUMO
Environmental temperature is thought to be directly sensed by neurons through their projections in the skin. A subset of the mammalian transient receptor potential (TRP) family of ion channels has been implicated in this process. These "thermoTRPs" are activated at distinct temperature thresholds and are typically expressed in sensory neurons. TRPV3 is activated by heat (>33 degrees C) and, unlike most thermoTRPs, is expressed in mouse keratinocytes. We found that TRPV3 null mice have strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, TRPV3 has a specific role in thermosensation. The natural compound camphor, which modulates sensations of warmth in humans, proved to be a specific activator of TRPV3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in TRPV3 null mice. Therefore, heat-activated receptors in keratinocytes are important for mammalian thermosensation.
Assuntos
Proteínas de Transporte de Cátions/fisiologia , Temperatura Alta , Canais Iônicos/fisiologia , Queratinócitos/metabolismo , Termorreceptores/fisiologia , Sensação Térmica , Animais , Bradicinina/farmacologia , Células CHO , Cânfora/farmacologia , Proteínas de Transporte de Cátions/genética , Células Cultivadas , Cricetinae , Derme/anatomia & histologia , Derme/inervação , Derme/ultraestrutura , Epiderme/anatomia & histologia , Epiderme/inervação , Epiderme/ultraestrutura , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Humanos , Canais Iônicos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Aferentes/fisiologia , Técnicas de Patch-Clamp , Canais de Cátion TRPV , Temperatura , Fatores de TempoRESUMO
Although mice lacking rod and cone photoreceptors are blind, they retain many eye-mediated responses to light, possibly through photosensitive retinal ganglion cells. These cells express melanopsin, a photopigment that confers this photosensitivity. Mice lacking melanopsin still retain nonvisual photoreception, suggesting that rods and cones could operate in this capacity. We observed that mice with both outer-retinal degeneration and a deficiency in melanopsin exhibited complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light. This indicates the importance of both nonvisual and classical visual photoreceptor systems for nonvisual photic responses in mammals.