RESUMO
Organization of immune responses requires exchange of information between cells. This is achieved through either direct cell-cell contacts and establishment of temporary synapses or the release of soluble factors, such as cytokines and chemokines. Here we show a novel form of cell-to-cell communication based on adenosine triphosphate (ATP). ATP released by stimulated T cells induces P2X4/P2X7-mediated calcium waves in the neighboring lymphocytes. Our data obtained in lymph node slices suggest that, during T-cell priming, ATP acts as a paracrine messenger to reduce the motility of lymphocytes and that this may be relevant to allow optimal tissue scanning by T cells.
Assuntos
Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Movimento Celular/imunologia , Modelos Imunológicos , Comunicação Parácrina/imunologia , Comunicação Parácrina/fisiologia , Linfócitos T/imunologia , Análise de Variância , Animais , Humanos , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real , Receptores Purinérgicos P2X/metabolismo , Linfócitos T/metabolismoRESUMO
Agrin, an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), is expressed by cells of the hematopoietic system but its role in leukocyte biology is not yet clear. Here we demonstrate that agrin has a crucial, nonredundant role in myeloid cell development and functions. We have identified lineage-specific alterations that affect maturation, survival and properties of agrin-deficient monocytic cells, and occur at stages later than stem cell precursors. Our data indicate that the cell-autonomous signals delivered by agrin are sensed by macrophages through the α-DC (DG) receptor and lead to the activation of signaling pathways resulting in rearrangements of the actin cytoskeleton during the phagocytic synapse formation and phosphorylation of extracellular signal-regulated kinases (Erk 1/2). Altogether, these data identify agrin as a novel player of innate immunity.
Assuntos
Agrina/metabolismo , Células Mieloides/citologia , Mielopoese , Agrina/análise , Agrina/genética , Animais , Sobrevivência Celular , Distroglicanas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/metabolismo , Células Mieloides/metabolismo , Fagocitose , FosforilaçãoRESUMO
Secretion of Amyloid-beta peptide (Abeta) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD). We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APP(sw) cell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of betaAPPs, Abeta fragments and Abeta circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy.