Macrophages are phagocytic cells that participate in a broad range of cellular functions and they are key regulators of innate immune responses and inflammation. Mitochondria are highly dynamic ...endosymbiotic organelles that play key roles in cellular metabolism and apoptosis. Mounting evidence suggests that mitochondria are involved in the interplay between metabolism and innate immune responses. The ability of these organelles to alter the metabolic profile of a cell, thereby allowing an appropriate response to each situation, is crucial for the correct establishment of immune responses. Furthermore, mitochondria act as scaffolds for many proteins involved in immune signaling pathways and as such they are able to modulate the function of these proteins. Finally, mitochondria release molecules, such as reactive oxygen species, which directly regulate the immune response. In summary, mitochondria can be considered as core components in the regulation of innate immune signaling. Here we discuss the intricate relationship between mitochondria, metabolism, intracellular signaling, and innate immune responses in macrophages.
Summary
Osteomyelitis is a bone infection caused mostly by Staphylococcus aureus but also by Gram‐negative bacteria. Toll‐like receptors (TLRs), after recognizing microbial products, induce a signal ...in neutrophils, leading to NF‐κB activation and transcription of pro‐inflammatory genes. Polymorphisms in TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) genes are associated with bacterial infections, we therefore studied these polymorphisms in osteomyelitis patients. Homozygotes for the TLR4 (Asp299Gly) polymorphism were significantly more frequent among the 80 osteomyelitis patients than in the 155 healthy controls (3/80, 3·8%versus 0/155, 0%; P = 0·038). Carriers of one or two G alleles of this tlr4 polymorphism were more likely to have Gram‐negative, haematogenous and/or chronic osteomyelitis than those without this mutation (P < 0·031). Patients with the TLR4 (Thr399Ile) mutant, which cosegregates with the TLR4 (Asp299Gly), were also carriers of this second polymorphism. No differences for the TLR2 (Arg753Gln) genotypes were found between patients and controls. Neutrophils of patients homozygous for the TLR4 (Asp299Gly) polymorphism showed lower LPS‐induced apoptosis reduction, phosphorylation of the inhibitor of NF‐κB, and lower IL‐6 and TNF‐α levels (P < 0·05). We report here for the first time an association between this TLR4 polymorphism and susceptibility to Gram‐negative bacteria and haematogenous osteomyelitis.
E2F1-3 proteins appear to have distinct roles in progenitor cells and in differentiating cells undergoing cell cycle exit. However, the function of these proteins in paradigms of terminal ...differentiation that involve continued cell division has not been examined. Using compound E2F1/E2F2-deficient mice, we have examined the effects of E2F1 and E2F2 loss on the differentiation and simultaneous proliferation of bone-marrow-derived cells toward the macrophage lineage. We show that E2F1/E2F2 deficiency results in accelerated DNA replication and cellular division during the initial cell division cycles of bone-marrow-derived cells, arguing that E2F1/E2F2 are required to restrain proliferation of pro-monocyte progenitors during their differentiation into macrophages, without promoting their cell cycle exit. Accelerated proliferation is accompanied by early expression of DNA replication and cell cycle regulators. Remarkably, rapid proliferation of E2F1/E2F2 compound mutant cultures is temporally followed by induction of a DNA damage response and the implementation of a p21(CIP1)-dependent senescence. We further show that differentiating E2F1/E2F2-knockout macrophages do not trigger a DNA damage response pathway in the absence of DNA replication. These findings underscore the relevance of E2F1 and E2F2 as suppressors of hematopoietic progenitor expansion. Our data indicate that their absence in differentiating macrophages initiates a senescence program that results from enforcement of a DNA damage response triggered by DNA hyper-replication.
To determine the effect of aging on IFN-gamma-induced MHC class II antigen expression, we produced bone marrow-derived macrophages in vitro. In these conditions, we analyzed the effect of aging on ...the genomic expression of macrophages without the influence of other cell types that may be affected by aging. Although macrophages from young and aged mice showed an identical degree of differentiation, after incubation with IFN-gamma, the expression at the cell surface of the IA complex and the levels of IAbeta protein and mRNA were lower in aged macrophages. Moreover, the transcription of the IAbeta gene was impaired in aged macrophages. The amount of transcription factors that bound to the W and X, but not to the Y, boxes of the IAbeta promoter gene was lower in aged macrophages. Similar levels of CIITA mRNA were found after IFN-gamma treatment of both young and aged macrophages. This shows that neither the initial cascade that starts after the interaction of IFN-gamma with the receptor nor the second signals involved in the expression of CIITA are impaired in aged macrophages. These data indicate that aging is associated with low levels of MHC class II gene induction by IFN-gamma because of impaired transcription.
Results from the first study of the regional air quality in Morelos state (located south of Mexico City) are presented. Criteria pollutants concentrations were measured at several sites within ...Morelos in February and March of 2007 and 2009; meteorological data was also collected along the state for the same time periods; additionally, a coupled meteorology–chemistry model (Mesoscale Climate Chemistry Model, MCCM) was used to gain understanding on the atmospheric processes occurring in the region. In general, concentrations of almost all the monitored pollutants (O3, NOx, CO, SO2, PM) remained below the Mexican air quality standards during the campaign; however, relatively high concentrations of ozone (8-hour average concentrations above the 60ppb level several times during the campaigns, i.e. exceeding the World Health Organization and the European Union maximum levels) were observed even at sites with very low reported local emissions. In fact, there is evidence that a large percentage of Morelos vegetation was probably exposed to unhealthy ozone levels (estimated AOT40 levels above the 3ppmh critical limit). The MCCM qualitatively reproduced ozone daily variations in the sites with an urban component; though it consistently overestimated the ozone concentration in all the sites in Morelos. This is probably because the lack of an updated and detailed emission inventory for the state. The main wind patterns in the region corresponded to the mountain–valley system (downslope flows at night and during the first hours of the day, and upslope flows in the afternoon). At times, Morelos was affected by emissions from surrounding states (Distrito Federal or Puebla). The results are indicative of an efficient transport of ozone and its precursors at a regional level. They also suggest that the state is divided in two atmospheric basins by the Sierras de Tepoztlán, Texcal and Monte Negro.
► First atmospheric study in the state of Morelos (south of Mexico City). ► Relatively high regional ozone concentrations were found. ► Most of the population might be exposed to unhealthy ozone levels. ► Critical AOT40 ozone levels are probably exceeded at a regional level. ► Transport of pollutants within the state is very efficient.
The genes of the transporter associated with antigen processing (Tap)-1, and the low molecular weight peptide (Lmp)-2, are crucial for class I major histocompatibility complex function and share a ...common bidirectional promoter. In murine bone marrow-derived macrophages, interferon gamma (IFN-gamma) induced Tap-1 and upregulated Lmp-2, which is constitutively expressed at low levels. The IFN-gamma-induction was independent of early gene synthesis. The mRNA induced by IFN-gamma was very stable. In macrophages from STAT1 knockout mice, IFN-gamma did not induce the expression of Tap-1 or Lmp-2. Several areas in the promoter can be controlled by IFN-gamma, such as proximal and distal GAS boxes in the direction of the Tap-1 gene, NFgammaB and IRF-1 boxes. By making deletions of the promoter, we found that only the proximal GAS and IRF-1 boxes are required for IFN-gamma induction of Tap-1 and Lmp-2. Experiments using nuclear extracts from macrophages treated for 30 min with IFN-gamma and gel shift analysis indicated that STAT1 binds to the GAS box. The nuclear extracts from macrophages treated for at least 2 h with IFN-gamma bound to the IRF-1 box. These results indicate that both STAT1 and IRF-1 are required for the IFN-gamma induction of Tap-1 and Lmp-2 genes.
Although all the cells in an organism contain the same genetic information, differences in the cell phenotype arise from the expression of lineage-specific genes. During myelopoiesis, external ...differentiating signals regulate the expression of a set of transcription factors. The combined action of these transcription factors subsequently determines the expression of myeloid-specific genes and the generation of monocytes and macrophages. In particular, the transcription factor PU.1 has a critical role in this process. We review the contribution of several transcription factors to the control of macrophage development.
Al final de la Edad Media, la situación de las iglesias parroquiales dependientes de los monasterios de San Zoilo de Carrión y San Román de Entrepeñas expresa el fin de un proceso desarrollado en los ...siglos anteriores. San Zoilo conservará el derecho a cobrar diezmos en un reducido número de lugares, pero a pesar de ello dichos diezmos serán una de sus principales fuentes de ingresos en la Edad Moderna. Por otra parte, la condición de los clérigos que sirven en las iglesias monásticas constituye un asunto de interés.
E2F1–3 proteins appear to have distinct roles in progenitor cells and in differentiating cells undergoing cell cycle exit. However, the function of these proteins in paradigms of terminal ...differentiation that involve continued cell division has not been examined. Using compound E2F1/E2F2-deficient mice, we have examined the effects of E2F1 and E2F2 loss on the differentiation and simultaneous proliferation of bone-marrow-derived cells toward the macrophage lineage. We show that E2F1/E2F2 deficiency results in accelerated DNA replication and cellular division during the initial cell division cycles of bone-marrow-derived cells, arguing that E2F1/E2F2 are required to restrain proliferation of pro-monocyte progenitors during their differentiation into macrophages, without promoting their cell cycle exit. Accelerated proliferation is accompanied by early expression of DNA replication and cell cycle regulators. Remarkably, rapid proliferation of E2F1/E2F2 compound mutant cultures is temporally followed by induction of a DNA damage response and the implementation of a p21CIP1-dependent senescence. We further show that differentiating E2F1/E2F2-knockout macrophages do not trigger a DNA damage response pathway in the absence of DNA replication. These findings underscore the relevance of E2F1 and E2F2 as suppressors of hematopoietic progenitor expansion. Our data indicate that their absence in differentiating macrophages initiates a senescence program that results from enforcement of a DNA damage response triggered by DNA hyper-replication.
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