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

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

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.

Authors

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

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Figure 2

Inhibition of BLT1, but not BLT2, improves host defense in diabetic mice during MRSA skin infection.

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Inhibition of BLT1, but not BLT2, improves host defense in diabetic mice...
(A) WT CT, STZ-treated WT, STZ-treated Alox5–/–, and STZ-treated Ltb4r1–/– mice were infected s.c. with MRSA, and infection areas were measured for 9 days. (B) Bacterial CFUs in the skin at day 9 after infection. Data are mean ± SEM of 5–10 mice. *P < 0.05 vs. WT CT mice. #P < 0.05 vs. STZ-treated WT mice. (C) CT and STZ-treated mice were infected s.c. with MRSA. STZ-treated mice were treated daily with topical ointments, vehicle-control, 0.001% BLT1 antagonist (U-75302), or 0.001% BLT2 antagonist (LY255283), and infection area was measured as in A. (D) Bacterial CFUs from mice in C at day 9 after infection. Data are mean ± SEM of 4–6 mice. *P < 0.05 vs. CT mice. #P < 0.05 vs. STZ-treated mice treated with vehicle control ointment. (E) Mice were infected s.c. with bioluminescent-expressing MRSA. Infection areas were measured every other day in CT and STZ-treated mice treated daily with vehicle control or 0.001% BLT1 antagonist (U-75302) ointments. (F) Bioluminescence imaging (BLI) to quantify bacterial burden in the skin at days 1, 3, 4, 7, and 9 after infection. (G) Representative images of bioluminescent MRSA infection in control and diabetic mice that were treated or not with BLT1 antagonist scanned by BLI. (H) Lesion size of nondiabetic NOD (ctNOD) and diabetic NOD (dbNOD) mice infected with MRSA by s.c. injection. Infected dbNOD mice were treated daily with vehicle-control or 0.001% BLT1 antagonist (U-75302) ointments as in C. Data are mean ± SEM of 5–10 mice. *P < 0.05 vs. CT mice. #P < 0.05 vs. STZ-treated mice treated with vehicle control. (I) Gram stains of CT and diabetic mice that were infected and treated with the BLT1 antagonist with MRSA for 1 and 9 after infection. Top panels show 100× and bottom panels show 1,000× magnification with an inset of a cropped zoomed view of 5 ,000× magnification. Arrows indicate bacteria.