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

Abstract

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), 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 cleavage in or WT mice that received WT bone marrow than in WT mice that received bone marrow. Intravital microscopy of the kidney in mice 5-6 days after UUO demonstrated the significant recruitment of GFP 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 CXCR1 renal phagocytes. , macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1, as well as the formation of AIM2 ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1 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.

Cell Death Pathways Drive Necroinflammation during Acute Kidney Injury

“…This format does not allow us to review this pathway in detail, as it has not been investigated in AKI yet. However, recent data suggest that it might be very important in AKI-chronic kidney disease (CKD) progression [2].…”

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

“…The role of these cytokines in driving CKD in an NLRP3‐dependent manner is well established , and the contribution of the AIM2 inflammasome in the production of these cytokines has only recently been suggested. This study demonstrated that Aim2 –/– macrophages that have engulfed necrotic cell DNA showed attenuated IL‐1β release . In this study, Aim2 –/– mice showed reduced renal injury, fibrosis and inflammation when compared with wild type littermates in a mouse model of unilateral urethral obstruction (UUO).…”

“…Inflammasome‐dependent cytokines IL‐18 and IL‐1β are shown to be detrimental during CKD in a mouse model of IRI . DNA from necrotic cells in the kidney is recognized by AIM2, leading to assembly of an inflammasome complex to produce IL‐1β and IL‐18 from macrophages during the pathogenesis of CKD . Likewise, AIM2 provides an inflammatory feedback loop during the progression of cardiovascular and neuroinflammatory diseases .…”

“…This is correlated with the reduced levels of the inflammasome effector cytokines IL‐β and IL‐18 found in the kidney samples from Aim2 –/– mice. A bone marrow chimera study suggests that AIM2 functions in the myeloid compartment in promoting the disease . Overall, these findings suggest that the necrotic DNA in the kidney is recognized by the AIM2 inflammasome to drive macrophage IL‐1β and IL‐18 release in the pathogenesis of CKD (Fig.…”

“…AIM2‐dependent effector cytokines and pyroptosis contribute to host protection against microbial infection . Although the AIM2 inflammasome is protective in infectious diseases, it is often detrimental in several sterile inflammatory diseases including atherosclerosis , chronic kidney disease (CKD) , skin disease , liver disease and neuroinflammation . In addition to these inflammasome‐dependent functions, AIM2 also inhibits colorectal tumorigenesis, which is independent of its inflammasome function.…”