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

PLoS One. 2015 Jun 26;10(6):e0131702. doi: 10.1371/journal.pone.0131702. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics*
  • Arthritis, Experimental / pathology
  • Autoantigens / metabolism
  • DNA / adverse effects
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Disease Models, Animal
  • Endodeoxyribonucleases / genetics*
  • Inflammasomes / genetics
  • Inflammasomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Interferon alpha-beta / genetics

Substances

  • Aim2 protein, mouse
  • Autoantigens
  • DNA-Binding Proteins
  • Ifnar1 protein, mouse
  • Inflammasomes
  • Receptor, Interferon alpha-beta
  • DNA
  • Endodeoxyribonucleases
  • deoxyribonuclease II

Grant support

This work was supported by grants from the German Research Foundation (SFB704 and SFB670) and the European Research Council (ERC‐2009‐StG 243046) to V.H. V.H. is member of the excellence cluster ImmunoSensation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.