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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

Gene expression of proinflammatory cytokines in joints of Dnase2 deficient mice relies on AIM2.A: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of cleaved Caspase-1, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. B: Cytokine levels of lysates as in (A) were determined. C and D: qPCR analysis of joints of the four different cohorts is shown for the indicated transcripts. The mRNA levels for the indicated cytokines are expressed relative to mRNA of HPRT1. 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.g003: Gene expression of proinflammatory cytokines in joints of Dnase2 deficient mice relies on AIM2.A: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of cleaved Caspase-1, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. B: Cytokine levels of lysates as in (A) were determined. C and D: qPCR analysis of joints of the four different cohorts is shown for the indicated transcripts. The mRNA levels for the indicated cytokines are expressed relative to mRNA of HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.

Mentions: While these data could not explain the positive impact of Aim2-deficiency in this mouse model, analyzing caspase-1 activation and cytokine expression in joints of Dnase2-deficient mice revealed a different picture. Compared to Dnase2-competent mice, joints of Aim2+/+x Dnase2-/- mice showed a marked increase in cleaved caspase-1, which was largely reduced in the absence of AIM2 (Fig 3A). Concomitant with this increased inflammasome activation, the expression of pro-inflammatory cytokines such as TNF, IL-6 and IL-1β expression was strongly increased both at protein, as well as at the mRNA level in joints of Dnase2-deficient mice (Fig 3B and 3C). Of note, the expression of these pro-inflammatory cytokines was reduced in the absence of Aim2. At the same time, diseased joints also displayed a robust induction of IFNβ and also interferon stimulated gens such as Aim2, Bst2 or Viperin were upregulated at the mRNA or protein level (Fig 3D and S2 Fig). This phenomenon can be explained by the fact that these genes are also directly induced upon cytosolic PRR stimulation, independently of the IFNAR loop [24]. Interestingly, the expression of these ISGs was also Aim2-dependent, most prominently IFNβ.


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

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

Gene expression of proinflammatory cytokines in joints of Dnase2 deficient mice relies on AIM2.A: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of cleaved Caspase-1, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. B: Cytokine levels of lysates as in (A) were determined. C and D: qPCR analysis of joints of the four different cohorts is shown for the indicated transcripts. The mRNA levels for the indicated cytokines are expressed relative to mRNA of HPRT1. 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.g003: Gene expression of proinflammatory cytokines in joints of Dnase2 deficient mice relies on AIM2.A: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of cleaved Caspase-1, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. B: Cytokine levels of lysates as in (A) were determined. C and D: qPCR analysis of joints of the four different cohorts is shown for the indicated transcripts. The mRNA levels for the indicated cytokines are expressed relative to mRNA of HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts.
Mentions: While these data could not explain the positive impact of Aim2-deficiency in this mouse model, analyzing caspase-1 activation and cytokine expression in joints of Dnase2-deficient mice revealed a different picture. Compared to Dnase2-competent mice, joints of Aim2+/+x Dnase2-/- mice showed a marked increase in cleaved caspase-1, which was largely reduced in the absence of AIM2 (Fig 3A). Concomitant with this increased inflammasome activation, the expression of pro-inflammatory cytokines such as TNF, IL-6 and IL-1β expression was strongly increased both at protein, as well as at the mRNA level in joints of Dnase2-deficient mice (Fig 3B and 3C). Of note, the expression of these pro-inflammatory cytokines was reduced in the absence of Aim2. At the same time, diseased joints also displayed a robust induction of IFNβ and also interferon stimulated gens such as Aim2, Bst2 or Viperin were upregulated at the mRNA or protein level (Fig 3D and S2 Fig). This phenomenon can be explained by the fact that these genes are also directly induced upon cytosolic PRR stimulation, independently of the IFNAR loop [24]. Interestingly, the expression of these ISGs was also Aim2-dependent, most prominently IFNβ.

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