Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice

Stephanie L. Brandt, Sue Wang, Naiara N. Dejani, Nathan Klopfenstein, Seth Winfree, Luciano Filgueiras, Brian P. McCarthy, Paul Territo, C. Henrique Serezani

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Poorly controlled diabetes leads to comorbidities and enhanced susceptibility to infections. While the immune components involved in wound healing in diabetes have been studied, the components involved in susceptibility to skin infections remain unclear. Here, we examined the effects of the inflammatory lipid mediator leukotriene B4 (LTB4) signaling through its receptor B leukotriene receptor 1 (BLT1) in the progression of methicillin-resistant Staphylococcus aureus (MRSA) skin infection in 2 models of diabetes. Diabetic mice produced higher levels of LTB4 in the skin, which correlated with larger nonhealing lesion areas and increased bacterial loads compared with nondiabetic mice. High LTB4 levels were also associated with dysregulated cytokine and chemokine production, excessive neutrophil migration but impaired abscess formation, and uncontrolled collagen deposition. Both genetic deletion and topical pharmacological BLT1 antagonism restored inflammatory response and abscess formation, followed by a reduction in the bacterial load and lesion area in the diabetic mice. Macrophage depletion in diabetic mice limited LTB4 production and improved abscess architecture and skin host defense. These data demonstrate that exaggerated LTB4/BLT1 responses mediate a derailed inflammatory milieu that underlies poor host defense in diabetes. Prevention of LTB4 production/actions could provide a new therapeutic strategy to restore host defense in diabetes.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number17
DOIs
StatePublished - Sep 6 2018
Externally publishedYes

Keywords

  • Bacterial infections
  • Dermatology
  • Eicosanoids
  • Inflammation
  • Macrophages

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    Brandt, S. L., Wang, S., Dejani, N. N., Klopfenstein, N., Winfree, S., Filgueiras, L., McCarthy, B. P., Territo, P., & Serezani, C. H. (2018). Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice. JCI insight, 3(17). https://doi.org/10.1172/jci.insight.120220