title: The Receptor for Advanced Glycation End Products Activates the AIM2 Inflammasome in Acute Pancreatitis.
abstract: Severe acute pancreatitis (AP) is responsible for significant human morbidity and mortality worldwide. Currently, no specific treatments for AP exist, primarily due to the lack of a mechanistic understanding of sterile inflammation and the resultant multisystem organ dysfunction, the pathologic response of AP linked to early death. In this study, we demonstrate that the class III major histocompatibility region III receptor for advanced glycation end products (RAGE) contributes to AP by modulating inflammasome activation in macrophages. RAGE mediated nucleosome-induced absent in melanoma 2 (but not NLRP3) inflammasome activation by modulating dsRNA-dependent protein kinase phosphorylation in macrophages. Pharmacological and genetic inhibition of the RAGE-dsRNA-dependent protein kinase pathway attenuated the release of inflammasome-dependent exosomal leaderless cytokines (e.g., IL-1β and high-mobility group box 1) in vitro. RAGE or absent in melanoma 2 depletion in mice limited tissue injury, reduced systemic inflammation, and protected against AP induced by l-arginine or cerulein in experimental animal models. These findings define a novel role for RAGE in the propagation of the innate immune response with activation of the nucleosome-mediated inflammasome and will help guide future development of therapeutic strategies to treat AP.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219; kangr@upmc.edu tangd2@upmc.edu zehh@upmc.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219;
authors.forename: Ruochan
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China; and.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China; and.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15219.
authors.forename: Michael T
authors.identifier: 0000-0003-3988-5419
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219; kangr@upmc.edu tangd2@upmc.edu zehh@upmc.edu.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219; kangr@upmc.edu tangd2@upmc.edu zehh@upmc.edu.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
mesh_terms: D000818:Animals; D001120:Arginine; D002108:Ceruletide; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D053208:Kaplan-Meier Estimate; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology; D009707:Nucleosomes / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000401:mortality*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: C000593873:Ager protein, mouse; C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009707:Nucleosomes; D000067759:Receptor for Advanced Glycation End Products; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002108:Ceruletide; D001120:Arginine