title: Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes.
abstract: Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced susceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), which triggers systemic inflammation that may increase susceptibility to polymicrobial sepsis. Consistent with chronic inflammation, peritoneal macrophages from two mouse models of T1DM had greater abundance of the adaptor MyD88 (myeloid differentiation factor 88) and its direct transcriptional effector STAT-1 (signal transducer and activator of transcription 1) than macrophages from nondiabetic mice. Expression of Alox5, which encodes 5-LO, and the concentration of the proinflammatory cytokine interleukin-1β (IL-1β) were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment reduced LTB4 concentrations in the circulation and Myd88 and Stat1 expression in the macrophages from T1DM mice. T1DM mice treated with a 5-LO inhibitor had reduced Myd88 mRNA in macrophages and increased abundance of IL-1 receptor antagonist and reduced production of IL-β in the circulation. T1DM mice lacking 5-LO or the receptor for LTB4 also produced less proinflammatory cytokines. Compared to wild-type or untreated diabetic mice, T1DM mice lacking the receptor for LTB4 or treated with a 5-LO inhibitor survived polymicrobial sepsis, had reduced production of proinflammatory cytokines, and had decreased bacterial counts. These results uncover a role for LTB4 in promoting sterile inflammation in diabetes and the enhanced susceptibility to sepsis in T1DM.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Immunology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508, Brazil.
authors: Luciano Ribeiro
authors: LR
authors: Filgueiras
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Stephanie L
authors: SL
authors: Brandt
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Soujuan
authors: S
authors: Wang
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Zhuo
authors: Z
authors: Wang
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: David L
authors: DL
authors: Morris
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Carmella
authors: C
authors: Evans-Molina
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Raghavendra G
authors: RG
authors: Mirmira
authors: Immunology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508, Brazil.
authors: Sonia
authors: S
authors: Jancar
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hserezan@iu.edu.
authors: C Henrique
authors: CH
authors: Serezani
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D015151:Immunoblotting; D007249:Inflammation / Q000150:complications* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007328:Insulin / Q000172:deficiency / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000209:etiology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase
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