title: RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis.
abstract: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and danger-associated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied.Acinetobacter baumanniiis an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models ofA. baumanniipneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE-/-mice systemically infected withA. baumanniiexhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE-/-mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE-/-mice results in decreased survival during systemicA. baumanniiinfection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Noto
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Becker
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: New York University Langone Medical Center, New York, New York, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA eric.skaar@vanderbilt.edu.|Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, Tennessee, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D000151:Acinetobacter Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology* / Q000401:mortality; D040981:Acinetobacter baumannii / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D016753:Interleukin-10
keywords: Acinetobacter baumannii; IL-10; RAGE; innate immunity; pneumonia; receptor for advanced glycation end products; sepsis