Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes

Luciano Ribeiro Filgueiras, Stephanie L. Brandt, Soujuan Wang, Zhuo Wang, David L. Morris, Carmella Evans-Molina, Raghu Mirmira, Sonia Jancar, C. Henrique Serezani

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)ra10
JournalScience Signaling
Volume8
Issue number361
DOIs
StatePublished - Jan 27 2015

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Leukotriene B4
Medical problems
Type 1 Diabetes Mellitus
Sepsis
Inflammation
Macrophages
Arachidonate 5-Lipoxygenase
Leukotriene B4 Receptors
Lipoxygenase Inhibitors
Peritoneal Macrophages
Cytokines
Myeloid Differentiation Factor 88
STAT1 Transcription Factor
Insulin
Interleukin-1 Receptors
Bacterial Load
Interleukin-1
Bacterial Infections
Lipids
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

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Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. / Filgueiras, Luciano Ribeiro; Brandt, Stephanie L.; Wang, Soujuan; Wang, Zhuo; Morris, David L.; Evans-Molina, Carmella; Mirmira, Raghu; Jancar, Sonia; Serezani, C. Henrique.

In: Science Signaling, Vol. 8, No. 361, 27.01.2015, p. ra10.

Research output: Contribution to journalArticle

Filgueiras, Luciano Ribeiro ; Brandt, Stephanie L. ; Wang, Soujuan ; Wang, Zhuo ; Morris, David L. ; Evans-Molina, Carmella ; Mirmira, Raghu ; Jancar, Sonia ; Serezani, C. Henrique. / Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. In: Science Signaling. 2015 ; Vol. 8, No. 361. pp. ra10.
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AU - Morris, David L.

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