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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

Swelling of joints in the context of Dnase2-deficiency is AIM2-dependent.A:Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice were scored for joint swelling at indicated time points in a blinded fashion. Statistical significance was assessed using a two-tailed Mann-Whitney test comparing Dnase2-/- cohorts at 8, 12 or 15 months. B: Representative pictures of fore-and hind pads of Aim2+/+ Dnase2-/- Ifnar1-/-, Aim2-/- Dnase2-/- Ifnar1-/-, Aim2+/+ Dnase2+/+ Ifnar1-/- and Aim2-/- Dnase2+/+ Ifnar1-/- mice at the age of 15 month are shown.
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pone.0131702.g001: Swelling of joints in the context of Dnase2-deficiency is AIM2-dependent.A:Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice were scored for joint swelling at indicated time points in a blinded fashion. Statistical significance was assessed using a two-tailed Mann-Whitney test comparing Dnase2-/- cohorts at 8, 12 or 15 months. B: Representative pictures of fore-and hind pads of Aim2+/+ Dnase2-/- Ifnar1-/-, Aim2-/- Dnase2-/- Ifnar1-/-, Aim2+/+ Dnase2+/+ Ifnar1-/- and Aim2-/- Dnase2+/+ Ifnar1-/- mice at the age of 15 month are shown.

Mentions: To study the contribution of AIM2 to Dnase2-deficiency triggered chronic polyarthritis, we crossed mice deficient in Aim2 with mice lacking Dnase2 and the common chain 1 of the type I IFN receptor (Aim2-/-, Dnase2-/-, Ifnar1-/-). As controls, mice deficient in Dnase2 and Ifnar1 (Aim2+/+, Dnase2-/-, Ifnar1-/-), deficient in Aim2 and Ifnar1 (Aim2-/-, Dnase2+/+, Ifnar1-/-) or only deficient in Ifnar1 (Aim2+/+, Dnase2+/+, Ifnar1-/-) were studied. For simplicity, the Ifnar1 genotype is not specifically referred to in the following, given the fact that all mice studied were deficient for Ifnar1. Mice of these genotypes were housed under specific pathogen free conditions and monitored for signs of polyarthritis. Consistent clinical signs of polyarthritis were observed around 8 months after birth. As such, Dnase2-deficient mice being wild type for Aim2 displayed a significant mean arthritis score of 1.8 compared to Dnase2-competent mice (Fig 1A). In the additional absence of Aim2, Dnase2-deficient mice (Aim2-/-x Dnase2-/-) showed a significant reduction in their signs of arthritis with a clinical score that was comparable to Dnase2-competent mice. With increasing age, signs of chronic polyarthritis progressed to a score of up to 3.4 in the Aim2+/+x Dnase2-/- cohort at 15 months, whereas Aim2-/-x Dnase2-/- mice showed greatly reduced signs of arthritis (mean score of 0.5). Of note, in line with previous reports, arthritis was more pronounced in fore pads than in hind pads (Fig 1B). Altogether, these results indicated that AIM2 is required for the development of polyarthritis in the context of DNase2-deficiency.


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

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

Swelling of joints in the context of Dnase2-deficiency is AIM2-dependent.A:Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice were scored for joint swelling at indicated time points in a blinded fashion. Statistical significance was assessed using a two-tailed Mann-Whitney test comparing Dnase2-/- cohorts at 8, 12 or 15 months. B: Representative pictures of fore-and hind pads of Aim2+/+ Dnase2-/- Ifnar1-/-, Aim2-/- Dnase2-/- Ifnar1-/-, Aim2+/+ Dnase2+/+ Ifnar1-/- and Aim2-/- Dnase2+/+ Ifnar1-/- mice at the age of 15 month are shown.
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Related In: Results  -  Collection

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pone.0131702.g001: Swelling of joints in the context of Dnase2-deficiency is AIM2-dependent.A:Aim2+/+Dnase2-/-Ifnar1-/-, Aim2-/-Dnase2-/-Ifnar1-/-, Aim2+/+Dnase2+/+Ifnar1-/-and Aim2-/-Dnase2+/+Ifnar1-/- mice were scored for joint swelling at indicated time points in a blinded fashion. Statistical significance was assessed using a two-tailed Mann-Whitney test comparing Dnase2-/- cohorts at 8, 12 or 15 months. B: Representative pictures of fore-and hind pads of Aim2+/+ Dnase2-/- Ifnar1-/-, Aim2-/- Dnase2-/- Ifnar1-/-, Aim2+/+ Dnase2+/+ Ifnar1-/- and Aim2-/- Dnase2+/+ Ifnar1-/- mice at the age of 15 month are shown.
Mentions: To study the contribution of AIM2 to Dnase2-deficiency triggered chronic polyarthritis, we crossed mice deficient in Aim2 with mice lacking Dnase2 and the common chain 1 of the type I IFN receptor (Aim2-/-, Dnase2-/-, Ifnar1-/-). As controls, mice deficient in Dnase2 and Ifnar1 (Aim2+/+, Dnase2-/-, Ifnar1-/-), deficient in Aim2 and Ifnar1 (Aim2-/-, Dnase2+/+, Ifnar1-/-) or only deficient in Ifnar1 (Aim2+/+, Dnase2+/+, Ifnar1-/-) were studied. For simplicity, the Ifnar1 genotype is not specifically referred to in the following, given the fact that all mice studied were deficient for Ifnar1. Mice of these genotypes were housed under specific pathogen free conditions and monitored for signs of polyarthritis. Consistent clinical signs of polyarthritis were observed around 8 months after birth. As such, Dnase2-deficient mice being wild type for Aim2 displayed a significant mean arthritis score of 1.8 compared to Dnase2-competent mice (Fig 1A). In the additional absence of Aim2, Dnase2-deficient mice (Aim2-/-x Dnase2-/-) showed a significant reduction in their signs of arthritis with a clinical score that was comparable to Dnase2-competent mice. With increasing age, signs of chronic polyarthritis progressed to a score of up to 3.4 in the Aim2+/+x Dnase2-/- cohort at 15 months, whereas Aim2-/-x Dnase2-/- mice showed greatly reduced signs of arthritis (mean score of 0.5). Of note, in line with previous reports, arthritis was more pronounced in fore pads than in hind pads (Fig 1B). Altogether, these results indicated that AIM2 is required for the development of polyarthritis in the context of DNase2-deficiency.

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