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AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

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).

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Authors and Affiliations

  1. Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai, 200032, China

    Weijuan Zhang, Yanxing Cai & Sidong Xiong

  2. Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, 199 Ren Ai Road, Suzhou, 215123, China

    Wei Xu, Xiaoming Gao & Sidong Xiong

  3. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Zhinan Yin

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  1. Weijuan Zhang
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  2. Yanxing Cai
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  3. Wei Xu
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Correspondence to Sidong Xiong.

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Weijuan Zhang and Yanxing Cai contributed equally to this work.

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Supplemental Figure 1

ApopDNA but not Un-apopDNA or OVA immunization upregulates AIM2 expression. Six- to 8-week-old female BALB/c mice were immunized with PBS, Un-apopDNA, apopDNA, or OVA (n = 10). (A and B) Real-time PCR analysis of AIM2 relative to GAPDH for PBMCs (A) or for CD11b+/F4/80high renal macrophages purified from the immunized mice (B). (C) Western blot analysis of AIM2 and GAPDH for aforementioned renal macrophages. (JPEG 18 kb)

High resolution image (TIFF 248 kb)

Supplemental Figure 2

ApopDNA is able to induce macrophage activation. (A) Macrophages were treated with Polymyxin B (Sigma) for 15 min before apopDNA transfection. Cytokine levels in the culture supernatants of macrophages were determined by ELISA assay. (B) ApopDNA was treated with DNase (Ambion) for 30 min at room temperature and then was transfected into macrophages. Cytokine levels in the culture supernatants of macrophages were determined by ELISA assay. (JPEG 42 kb)

High resolution image (TIFF 557 kb)

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Zhang, W., Cai, Y., Xu, W. et al. AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation. J Clin Immunol 33, 925–937 (2013). https://doi.org/10.1007/s10875-013-9881-6

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  • DOI: https://doi.org/10.1007/s10875-013-9881-6

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