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AIM2 Drives Joint Inflammation in a Self-DNA Triggered Model of Chronic Polyarthritis.

Jakobs C, Perner S, Hornung V - PLoS ONE (2015)

Bottom Line: This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints.Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2.Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.

ABSTRACT
Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.

No MeSH data available.


Related in: MedlinePlus

Systemic proinflammatory status in Dnase2-/- mice is independent of AIM2.A: Serum was collected from Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice at the age of 15 month and analyzed for the depicted cytokines. B: Spleen weight and representative pictures of spleens from mice at the age of 15 month. C: Relative IFNβ gene expression in spleen tissue normalized to the expression level of HPRT1 is shown. D: Anti-cyclic citrullinated peptide antibody (Anti-CCP-AB) was measured in serum samples as in (A). Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.
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pone.0131702.g002: Systemic proinflammatory status in Dnase2-/- mice is independent of AIM2.A: Serum was collected from Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice at the age of 15 month and analyzed for the depicted cytokines. B: Spleen weight and representative pictures of spleens from mice at the age of 15 month. C: Relative IFNβ gene expression in spleen tissue normalized to the expression level of HPRT1 is shown. D: Anti-cyclic citrullinated peptide antibody (Anti-CCP-AB) was measured in serum samples as in (A). Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.

Mentions: As mentioned above, it has been proposed that joint inflammation in this mouse model is driven by systemic inflammation. Therefore, to elucidate the mechanism of Aim2-deficiency ameliorating DNase2-/--associated polyarthritis, we next assessed systemic signs of inflammation in these mice. Dnase2-deficient mice showed markedly increased levels of TNF and IL-10 in serum, however, this was observed irrespective of their Aim2 genotype (Fig 2A). Surprisingly, levels of the disease-relevant cytokines IL-6 and IL-1β were not elevated in serum of Dnase2-/- animals (Fig 2A) and cytokines associated with increased activation of the adaptive branch of the immune system (e.g. IL-2, IL-4 or IFNγ) were also not significantly increased above background level (data not shown). Dnase2-deficient mice developed marked splenomegaly, with spleen sizes being 4–5 fold increased compared to control animals (Fig 2B). However, as observed for serum levels of TNF and IL-10, the absence of AIM2 had no impact on this phenomenon. Spleen enlargement was associated with an increased expression of IFNβ in splenic tissue (Fig 2C), again being independent of the Aim2 genotype. Moreover, anti-cyclic citrullinated peptide antibodies were also observed in Dnase2-deficient mice irrespective of their Aim2 genotype (Fig 2D).


AIM2 Drives Joint Inflammation in a Self-DNA Triggered Model of Chronic Polyarthritis.

Jakobs C, Perner S, Hornung V - PLoS ONE (2015)

Systemic proinflammatory status in Dnase2-/- mice is independent of AIM2.A: Serum was collected from Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice at the age of 15 month and analyzed for the depicted cytokines. B: Spleen weight and representative pictures of spleens from mice at the age of 15 month. C: Relative IFNβ gene expression in spleen tissue normalized to the expression level of HPRT1 is shown. D: Anti-cyclic citrullinated peptide antibody (Anti-CCP-AB) was measured in serum samples as in (A). Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482750&req=5

pone.0131702.g002: Systemic proinflammatory status in Dnase2-/- mice is independent of AIM2.A: Serum was collected from Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice at the age of 15 month and analyzed for the depicted cytokines. B: Spleen weight and representative pictures of spleens from mice at the age of 15 month. C: Relative IFNβ gene expression in spleen tissue normalized to the expression level of HPRT1 is shown. D: Anti-cyclic citrullinated peptide antibody (Anti-CCP-AB) was measured in serum samples as in (A). Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.
Mentions: As mentioned above, it has been proposed that joint inflammation in this mouse model is driven by systemic inflammation. Therefore, to elucidate the mechanism of Aim2-deficiency ameliorating DNase2-/--associated polyarthritis, we next assessed systemic signs of inflammation in these mice. Dnase2-deficient mice showed markedly increased levels of TNF and IL-10 in serum, however, this was observed irrespective of their Aim2 genotype (Fig 2A). Surprisingly, levels of the disease-relevant cytokines IL-6 and IL-1β were not elevated in serum of Dnase2-/- animals (Fig 2A) and cytokines associated with increased activation of the adaptive branch of the immune system (e.g. IL-2, IL-4 or IFNγ) were also not significantly increased above background level (data not shown). Dnase2-deficient mice developed marked splenomegaly, with spleen sizes being 4–5 fold increased compared to control animals (Fig 2B). However, as observed for serum levels of TNF and IL-10, the absence of AIM2 had no impact on this phenomenon. Spleen enlargement was associated with an increased expression of IFNβ in splenic tissue (Fig 2C), again being independent of the Aim2 genotype. Moreover, anti-cyclic citrullinated peptide antibodies were also observed in Dnase2-deficient mice irrespective of their Aim2 genotype (Fig 2D).

Bottom Line: This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints.Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2.Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.

ABSTRACT
Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand-dependent autoinflammatory condition.

No MeSH data available.


Related in: MedlinePlus