AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation
- 1.2k Downloads
Lupus nephritis, a major cause of morbidity in patients with systemic lupus erythematosus (SLE), is generally thought to be induced by macrophage-mediated inflammation following deposition of various autoantibodies in kidneys. We previously reported that macrophage aberrant activation induced by activated lymphocyte-derived apoptotic DNA (apopDNA) have been found to play pathogenic roles in the immunodysregulation in lupus nephritis. However, DNA sensor(s) involved in apopDNA-induced macrophage activation and lupus nephritis remains largely undefined. Herein, we aimed to reveal the DNA sensor(s) involved in SLE disease.
Correlation between the level of absent in melanoma 2 (AIM2), a cytoplasmic DNA receptor in the inflammasome pathway, and the clinical severity of SLE disease were analyzed in SLE patients as well as in lupus mice. Activated macrophages induced by apopDNA were analyzed by real-time PCR and western blot for AIM2 expression. After silencing of AIM2 via siRNA-mediated knockdown in vitro and in vivo, macrophage activation, inflammatory response, and SLE syndrome were assessed.
AIM2 expression was closely correlated with the severity of disease in SLE patients and in lupus mice. Importantly, AIM2 expression was significantly increased in apopDNA-induced macrophages and closely correlated with macrophage activation. Knockdown of AIM2 significantly blunted apopDNA-induced macrophage activation. Furthermore, blockade of AIM2 expression notably ameliorated SLE syndrome via impeding macrophage activation and dampening inflammatory response in apopDNA-induced lupus mice.
Our results implied that AIM2 might act as an important DNA sensor and a potential biomarker for apopDNA-induced macrophage functional maturation and SLE disease.
KeywordsSLE lupus nephritis macrophage activation DNA sensor AIM2 inflammation
The authors apologize for the inability to cite all related and important literature due to space limitations. We thank Prof Nan Shen (Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China) for SLE patient samples collection. This work was supported by grants of National Natural Science Foundation of China (30890141, 31100629, 31270863, 81273300), Major State Basic Research Development Program of China (2013CB530501), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, IRT1075), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD),, Shanghai STC grant (10JC1401400), and Postdoctoral Science Foundation of China (2012T50374).
- 50.Panchanathan R, Shen H, Duan X, Rathinam VA, Erickson LD, Fitzgerald KA, et al. Aim2 deficiency in mice suppresses the expression of the inhibitory Fcgamma receptor (FcgammaRIIB) through the induction of the IFN-inducible p202, a lupus susceptibility protein. J Immunol. 2011;186(12):6762–70.PubMedCrossRefGoogle Scholar