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Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages.

Navasa N, Martin-Ruiz I, Atondo E, Sutherland JD, Angel Pascual-Itoiz M, Carreras-González A, Izadi H, Tomás-Cortázar J, Ayaz F, Martin-Martin N, Torres IM, Barrio R, Carracedo A, Olivera ER, Rincón M, Anguita J - Sci Rep (2015)

Bottom Line: IFNγ, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages.The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression.These results identify the MCJ gene as a transcriptional target of IFNγ and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.

ABSTRACT
MCJ (DNAJC15) is a mitochondrial protein that regulates the mitochondrial metabolic status of macrophages and their response to inflammatory stimuli. CpG island methylation in cancer cells constitutes the only mechanism identified for the regulation of MCJ gene expression. However, whether DNA methylation or transcriptional regulation mechanisms are involved in the physiological control of this gene expression in non-tumor cells remains unknown. We now demonstrate a mechanism of regulation of MCJ expression that is independent of DNA methylation. IFNγ, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages. The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression. These results identify the MCJ gene as a transcriptional target of IFNγ and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions.

No MeSH data available.


Related in: MedlinePlus

Heart-infiltrating macrophages do not express MCJ upon infection with B. burgdorferi.The base of the hearts of 3 week infected and uninfected (UI) mice were used to extract RNA and assess macrophage infiltration and TNF expression levels by qRT-PCR using primers specific for F4/80 (A) or TNF (B). NS; Not significant. (C) Macrophages were purified from the hearts of 3-week infected B6 mice and used to extract RNA. qRT-PCR was then performed to detect MCJ mRNA levels, compared to bone marrow-derived macrophages (BMM). As a control, MCJ mRNA levels were also determined in whole heart tissue of 3-week infected mice. The data shown correspond to 5 mice per group and are presented as the mean ± SE. *; Student´s t test, p < 0.05.
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f1: Heart-infiltrating macrophages do not express MCJ upon infection with B. burgdorferi.The base of the hearts of 3 week infected and uninfected (UI) mice were used to extract RNA and assess macrophage infiltration and TNF expression levels by qRT-PCR using primers specific for F4/80 (A) or TNF (B). NS; Not significant. (C) Macrophages were purified from the hearts of 3-week infected B6 mice and used to extract RNA. qRT-PCR was then performed to detect MCJ mRNA levels, compared to bone marrow-derived macrophages (BMM). As a control, MCJ mRNA levels were also determined in whole heart tissue of 3-week infected mice. The data shown correspond to 5 mice per group and are presented as the mean ± SE. *; Student´s t test, p < 0.05.

Mentions: During short-term in vivo inflammatory conditions, MCJ regulates the response of macrophages to Staphylococcus aureus as well as LPS treatment in mice sensitized with galactosamine 7. In order to determine the role of MCJ on the local macrophage response during an infectious process that requires a more complex and long lasting interaction between the pathogen and the host, we infected MCJ KO and WT mice with Borrelia burgdorferi. After 3 weeks of infection, macrophage infiltration was not significantly different in infected MCJ KO mice and WT animals (Fig. 1A). In addition, the amount of TNF expressed in the cardiac tissue upon infection was not altered in the absence or presence of MCJ (Fig. 1B). We also assessed the level of expression of MCJ in heart-infiltrating macrophages at the peak of infection with the spirochete. Surprisingly, in contrast to bone marrow-derived macrophages (BMMs), real time RT-PCR failed to detect appreciable levels of MCJ mRNA in macrophages infiltrating the hearts (Fig. 1C). The downregulation of MCJ expression during infection was selective of macrophages since total heart MCJ expression levels were readily detected in the infected mice (Fig. 1C). The histological analysis of infected joint and heart tissue showed that the degree of cardiac inflammation was not affected by the lack of the MCJ gene (Fig. S1A,B). Furthermore, the levels of spirochetal DNA were similar in WT and MCJ KO mice (Fig. S1C). These results suggested that upon infection with B. burgdorferi, MCJ expression is repressed specifically in macrophages infiltrating the heart.


Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages.

Navasa N, Martin-Ruiz I, Atondo E, Sutherland JD, Angel Pascual-Itoiz M, Carreras-González A, Izadi H, Tomás-Cortázar J, Ayaz F, Martin-Martin N, Torres IM, Barrio R, Carracedo A, Olivera ER, Rincón M, Anguita J - Sci Rep (2015)

Heart-infiltrating macrophages do not express MCJ upon infection with B. burgdorferi.The base of the hearts of 3 week infected and uninfected (UI) mice were used to extract RNA and assess macrophage infiltration and TNF expression levels by qRT-PCR using primers specific for F4/80 (A) or TNF (B). NS; Not significant. (C) Macrophages were purified from the hearts of 3-week infected B6 mice and used to extract RNA. qRT-PCR was then performed to detect MCJ mRNA levels, compared to bone marrow-derived macrophages (BMM). As a control, MCJ mRNA levels were also determined in whole heart tissue of 3-week infected mice. The data shown correspond to 5 mice per group and are presented as the mean ± SE. *; Student´s t test, p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588509&req=5

f1: Heart-infiltrating macrophages do not express MCJ upon infection with B. burgdorferi.The base of the hearts of 3 week infected and uninfected (UI) mice were used to extract RNA and assess macrophage infiltration and TNF expression levels by qRT-PCR using primers specific for F4/80 (A) or TNF (B). NS; Not significant. (C) Macrophages were purified from the hearts of 3-week infected B6 mice and used to extract RNA. qRT-PCR was then performed to detect MCJ mRNA levels, compared to bone marrow-derived macrophages (BMM). As a control, MCJ mRNA levels were also determined in whole heart tissue of 3-week infected mice. The data shown correspond to 5 mice per group and are presented as the mean ± SE. *; Student´s t test, p < 0.05.
Mentions: During short-term in vivo inflammatory conditions, MCJ regulates the response of macrophages to Staphylococcus aureus as well as LPS treatment in mice sensitized with galactosamine 7. In order to determine the role of MCJ on the local macrophage response during an infectious process that requires a more complex and long lasting interaction between the pathogen and the host, we infected MCJ KO and WT mice with Borrelia burgdorferi. After 3 weeks of infection, macrophage infiltration was not significantly different in infected MCJ KO mice and WT animals (Fig. 1A). In addition, the amount of TNF expressed in the cardiac tissue upon infection was not altered in the absence or presence of MCJ (Fig. 1B). We also assessed the level of expression of MCJ in heart-infiltrating macrophages at the peak of infection with the spirochete. Surprisingly, in contrast to bone marrow-derived macrophages (BMMs), real time RT-PCR failed to detect appreciable levels of MCJ mRNA in macrophages infiltrating the hearts (Fig. 1C). The downregulation of MCJ expression during infection was selective of macrophages since total heart MCJ expression levels were readily detected in the infected mice (Fig. 1C). The histological analysis of infected joint and heart tissue showed that the degree of cardiac inflammation was not affected by the lack of the MCJ gene (Fig. S1A,B). Furthermore, the levels of spirochetal DNA were similar in WT and MCJ KO mice (Fig. S1C). These results suggested that upon infection with B. burgdorferi, MCJ expression is repressed specifically in macrophages infiltrating the heart.

Bottom Line: IFNγ, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages.The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression.These results identify the MCJ gene as a transcriptional target of IFNγ and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary and Animal Sciences. University of Massachusetts Amherst. Amherst, MA 01003.

ABSTRACT
MCJ (DNAJC15) is a mitochondrial protein that regulates the mitochondrial metabolic status of macrophages and their response to inflammatory stimuli. CpG island methylation in cancer cells constitutes the only mechanism identified for the regulation of MCJ gene expression. However, whether DNA methylation or transcriptional regulation mechanisms are involved in the physiological control of this gene expression in non-tumor cells remains unknown. We now demonstrate a mechanism of regulation of MCJ expression that is independent of DNA methylation. IFNγ, a protective cytokine against cardiac inflammation during Lyme borreliosis, represses MCJ transcription in macrophages. The transcriptional regulator, Ikaros, binds to the MCJ promoter in a Casein kinase II-dependent manner, and mediates the repression of MCJ expression. These results identify the MCJ gene as a transcriptional target of IFNγ and provide evidence of the dynamic adaptation of normal tissues to changes in the environment as a way to adapt metabolically to new conditions.

No MeSH data available.


Related in: MedlinePlus