title: Tissue damage negatively regulates LPS-induced macrophage necroptosis.
abstract: Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mφ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mφ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mφ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mφ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.|Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Scott
authors.affiliation: University of Pittsburgh School of Arts and Science, Pittsburgh, PA 15213, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen 518055, China.|Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fan
mesh_terms: D000067531:Alarmins / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D050723:Fractures, Bone / Q000378:metabolism / Q000473:pathology*; D024243:HMGB1 Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009336:Necrosis / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000067531:Alarmins; D000590:Amino Acid Chloromethyl Ketones; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D018696:Neuroprotective Agents; D000067759:Receptor for Advanced Glycation End Products; D051197:Toll-Like Receptor 4; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone