HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation through RAGE
- Biochem Biophys Res Commun. 2014 Jul 18;450(1):851-6. doi: 10.1016/j.bbrc.2014.06.074.
- 1. Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
- 2. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
- 3. Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15219, USA.
- 4. Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
- 5. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15219, USA.
- 6. The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
- 7. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
- 8. Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15219, USA. Electronic address: [email protected].
High mobility group box 1 (HMGB1) is a prototype damage-associated molecular pattern (DAMP) that can induce inflammatory and immune responses alone as well as in combination with Other molecules such as DNA. However, the intricate molecular mechanisms underlying HMGB1-DNA complex-mediated innate immune response remains largely elusive. In this study, we demonstrated that HMGB1-DNA complex initially induced absent in melanoma 2 (AIM2)-dependent inflammasome activation, and promoted rapid release of inflammasome-dependent early proinflammatory cytokines such as interleukin 1β (IL-1β). Subsequently, HMGB1-DNA complex stimulated an ATG5-dependent cellular degradation process, Autophagy, which was paralleled by a cessation of AIM2 inflammasome activation and IL-1β release. These HMGB1-DNA complex-induced inflammasome activation and Autophagy were both dependent on the receptor for advanced glycation endproducts (RAGE) that recognizes a wide array of ligands (including HMGB1 and DNA). Thus, Autophagy may function as a negative counter-regulatory mechanism for HMGB1-DNA complex-induced inflammasome activation, and provide a checkpoint to limit the development of inflammation.