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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

Local inflammation of joints in Dnase2 deficient mice is largely AIM2 dependent.A: Joint sections of 15 month old mice of the depicted genotypes were stained with haematoxylin/eosin, F4/80 and MMP3. B, Bone; BM, Bone marrow; C, cartilage; I, Infiltrate; S, Synovitis. B: Histological scores of joint sections from 15 month old mice stained with HE, F4/80 or MMP3: 0, no overt signs of synovitis / infiltration; 1, low grade synovitis / infiltration; 2, intermediate grade synovitis / infiltration; 3, high grade synovitis / infiltration. C: RNAs were isolated from the joints of 15 months old mice to quantify MMP3 expression normalized to HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts. D: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of MMP3, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed Mann-Whitney test (b) or using a two-tailed, unpaired t-test (c) comparing the Dnase2-/- cohorts.
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pone.0131702.g004: Local inflammation of joints in Dnase2 deficient mice is largely AIM2 dependent.A: Joint sections of 15 month old mice of the depicted genotypes were stained with haematoxylin/eosin, F4/80 and MMP3. B, Bone; BM, Bone marrow; C, cartilage; I, Infiltrate; S, Synovitis. B: Histological scores of joint sections from 15 month old mice stained with HE, F4/80 or MMP3: 0, no overt signs of synovitis / infiltration; 1, low grade synovitis / infiltration; 2, intermediate grade synovitis / infiltration; 3, high grade synovitis / infiltration. C: RNAs were isolated from the joints of 15 months old mice to quantify MMP3 expression normalized to HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts. D: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of MMP3, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed Mann-Whitney test (b) or using a two-tailed, unpaired t-test (c) comparing the Dnase2-/- cohorts.

Mentions: At 15 months of age, joints of Aim2+/+x Dnase2-/- mice showed severe signs of synovitis with hyperproliferation of synovial cells and massive immune cell infiltration, associated with pannus formation, cartilage destruction and bone erosion (Fig 4A and 4B). The immune cell infiltrate, most prominently pannus formation, was mainly dominated by the presence of macrophages, as revealed by F4/80 immunohistochemistry. Moreover, as a quantitative measure of local catabolic activity, expression of matrix metalloproteinase-3 (Mmp3) was strongly induced in joints of Aim2+/+x Dnase2-/- animals as observed by immunohistochemistry (Fig 4A and 4B) and also by qPCR and immunoblotting of joint sections (Fig 4C and 4D). In line with the arthritis scores and the pro-inflammatory cytokine profile, histological signs of arthritis, macrophage infiltration and Mmp3 expression were largely decreased in the absence of Aim2.


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

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

Local inflammation of joints in Dnase2 deficient mice is largely AIM2 dependent.A: Joint sections of 15 month old mice of the depicted genotypes were stained with haematoxylin/eosin, F4/80 and MMP3. B, Bone; BM, Bone marrow; C, cartilage; I, Infiltrate; S, Synovitis. B: Histological scores of joint sections from 15 month old mice stained with HE, F4/80 or MMP3: 0, no overt signs of synovitis / infiltration; 1, low grade synovitis / infiltration; 2, intermediate grade synovitis / infiltration; 3, high grade synovitis / infiltration. C: RNAs were isolated from the joints of 15 months old mice to quantify MMP3 expression normalized to HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts. D: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of MMP3, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed Mann-Whitney test (b) or using a two-tailed, unpaired t-test (c) comparing the Dnase2-/- cohorts.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131702.g004: Local inflammation of joints in Dnase2 deficient mice is largely AIM2 dependent.A: Joint sections of 15 month old mice of the depicted genotypes were stained with haematoxylin/eosin, F4/80 and MMP3. B, Bone; BM, Bone marrow; C, cartilage; I, Infiltrate; S, Synovitis. B: Histological scores of joint sections from 15 month old mice stained with HE, F4/80 or MMP3: 0, no overt signs of synovitis / infiltration; 1, low grade synovitis / infiltration; 2, intermediate grade synovitis / infiltration; 3, high grade synovitis / infiltration. C: RNAs were isolated from the joints of 15 months old mice to quantify MMP3 expression normalized to HPRT1. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed, unpaired t-test comparing the Dnase2-/- cohorts. D: Protein lysates were generated from the joints of 15 months old mice and immunoblotted for the presence of MMP3, whereas β-Actin served as a loading control. Three independent protein lysates were analyzed per cohort. Data are presented as mean values + SEM, whereas statistical significance was assessed using a two-tailed Mann-Whitney test (b) or using a two-tailed, unpaired t-test (c) comparing the Dnase2-/- cohorts.
Mentions: At 15 months of age, joints of Aim2+/+x Dnase2-/- mice showed severe signs of synovitis with hyperproliferation of synovial cells and massive immune cell infiltration, associated with pannus formation, cartilage destruction and bone erosion (Fig 4A and 4B). The immune cell infiltrate, most prominently pannus formation, was mainly dominated by the presence of macrophages, as revealed by F4/80 immunohistochemistry. Moreover, as a quantitative measure of local catabolic activity, expression of matrix metalloproteinase-3 (Mmp3) was strongly induced in joints of Aim2+/+x Dnase2-/- animals as observed by immunohistochemistry (Fig 4A and 4B) and also by qPCR and immunoblotting of joint sections (Fig 4C and 4D). In line with the arthritis scores and the pro-inflammatory cytokine profile, histological signs of arthritis, macrophage infiltration and Mmp3 expression were largely decreased in the absence of Aim2.

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