Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

<jats:p>Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), <jats:italic toggle="yes">Aim2</jats:italic> deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1<jats:italic toggle="yes">β</jats:italic> cleavage in <jats:italic toggle="yes">Aim2</jats:italic> <jats:sup>−/−</jats:sup> or WT mice that received WT bone marrow than in WT mice that received <jats:italic toggle="yes">Aim2</jats:italic> <jats:sup>−/−</jats:sup> bone marrow. Intravital microscopy of the kidney in <jats:italic toggle="yes">LysM(gfp/gfp) </jats:italic> mice 5–6 days after UUO demonstrated the significant recruitment of GFP<jats:sup>+</jats:sup> proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX<jats:sub>3</jats:sub>CR1<jats:sup>+</jats:sup> renal phagocytes. <jats:italic toggle="yes">In vitro</jats:italic>, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1<jats:italic toggle="yes">β</jats:italic>, as well as the formation of AIM2<jats:sup>+</jats:sup> ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1<jats:italic toggle="yes">β</jats:italic> levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.</jats:p>