RESUMEN
Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.
Asunto(s)
Anemia/fisiopatología , Síndrome de Activación Macrofágica/fisiopatología , Glicoproteínas de Membrana/fisiología , Fagocitos/citología , Transducción de Señal , Receptor Toll-Like 7/fisiología , Receptor Toll-Like 9/fisiología , Animales , Diferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/fisiología , Inflamación/fisiopatología , Factores Reguladores del Interferón/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Factor 88 de Diferenciación Mieloide/fisiología , Plasmodium yoelii , Bazo/citología , Trombocitopenia/fisiopatología , TranscriptomaRESUMEN
Release of inflammatory monocytes from the bone marrow (BM) into the blood is an important physiological response to infection, but the mechanisms regulating this phenomenon during viral infection are not completely defined. Here, we show that low-dose infection with lymphocytic choriomeningitis virus (LCMV) caused rapid, transient inflammatory monocytosis that required type I interferon (IFN) and Toll-like receptor (TLR) 7 signaling. Type I IFN and TLR7 signals were critical for induction of IFN-stimulated gene expression and CCR2 ligand upregulation in the BM microenvironment in response to LCMV infection. Experiments utilizing BM chimeric mice demonstrated that type I IFN and TLR7 signaling on either hematopoietic or nonhematopoietic cells was sufficient to initiate monocytosis in response to LCMV infection. BM plasmacytoid dendritic cells (pDCs) generated type I IFN directly ex vivo, suggesting that pDCs are a hematopoietic contributor of type I IFN in the BM early during LCMV infection. Overall, we describe novel roles for type I IFN and TLR7 signaling in nonhematopoietic cells and BM pDCs in directing IFN-stimulated gene and CCR2 ligand expression in the BM to initiate an increase in blood inflammatory monocytes during viral infection.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Interferón Tipo I/inmunología , Virus de la Coriomeningitis Linfocítica , Glicoproteínas de Membrana/inmunología , Monocitos/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 7/inmunología , Animales , Infecciones por Arenaviridae/sangre , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.
Asunto(s)
Trastorno Bipolar/genética , Predisposición Genética a la Enfermedad , Animales , Conducta Animal/fisiología , Trastorno Bipolar/fisiopatología , Cromatina/metabolismo , Modelos Animales de Enfermedad , Redes Reguladoras de Genes/genética , Genoma Humano/genética , Humanos , Ratones , Actividad Motora/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Neurotensin (NT) is a 13 amino acid neuropeptide that is identical in mice and humans and is released from and acts upon a number of social brain regions. Recent work indicates NT neurotransmission may be altered in postpartum females and support the onset of some maternal behaviors. In a recent study, we highlighted how virgin and postpartum brains from mice selected for high offspring protection differ in response to injected NT (0.1 µg) relative to vehicle when examining c-Fos profiles across the CNS. In this companion study we use a second marker for brain activity, Egr-1, and evaluate multiple brain regions. Common significant increased Egr-1 responses to NT (relative to vehicle) were found in both female groups only in ventromedial hypothalamus. In lateral periaqueductal gray, virgin mice showed a significant Egr-1 increase with NT (relative to vehicle), but maternal mice did not. When comparing NT injections, virgin (relative to maternal) mice had significantly higher activity in five regions, including anterior hypothalamus, lateral hypothalamus, somatosensory cortex, paraventricular nucleus, and zona incerta; no regions were higher in maternal mice. A Principal Components Analysis was also used for data mining and in virgin mice, greater changes in activity hubs were found with NT (relative to vehicle) than for maternal mice. Overall, a lower sensitivity to NT in terms of Egr-1 reactivity in the maternal state was highlighted and this is consistent with previous c-Fos results. These findings provide additional insight into the mechanisms by which NT functions in the CNS.
Asunto(s)
Química Encefálica/fisiología , Encéfalo/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Conducta Materna/fisiología , Neurotensina/administración & dosificación , Periodo Posparto/metabolismo , Animales , Encéfalo/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Femenino , Inyecciones Intraventriculares , Conducta Materna/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Periodo Posparto/efectos de los fármacos , Embarazo , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.