Browsing by Subject "Leukotriene"

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    Leukotriene B4 levels determine staphylococcus aureus skin infection outcome
    (2017-08-18) Brandt, Stephanie Lillian; Serezani, Henrique; Blum, Janice; Kaplan, Mark H.; Evans-Molina, Carmella
    Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of severe skin infections and due to antibiotic resistance there is an intrinsic need to develop new immunotherapeutic strategies. Skin immune responses to infections require the cross-talk between phagocytes and structural cells that involves the secretion of cytokines, chemokines, and lipids. Leukotriene B4 (LTB4) is a pleiotropic lipid mediator known as a chemoattractant, but is also necessary to promote antimicrobial activity through B leukotriene receptor 1 (BLT1) signaling. However, chronic LTB4 production is associated with inflammatory diseases, including diabetes. People with diabetes are more susceptible to infections. The determinants by which LTB4/BLT1 promotes protective or detrimental immune responses in homeostasis and diabetes are unknown. We hypothesize that LTB4 levels determine infection outcome; while LTB4 is necessary for infection control, excessive LTB4 levels promote overwhelming inflammation that impairs host defense. Our data show that skin macrophages were necessary for LTB4 production and that LTB4 was vital for neutrophil direction, abscess formation, IL 1β production, and MRSA clearance through reactive oxygen species production. Importantly, topical LTB4 ointment treatment enhances neutrophil direction, abscess formation, and bacterial clearance. Conversely, in the setting of diabetes, skin macrophages drove excessive LTB4 production that promoted overwhelming inflammation, uncontrolled neutrophil recruitment, poor abscess formation, and lack of bacterial control. Diabetic mice treated with a topical ointment to inhibit BLT1 dampened inflammation and restored host defense by improving abscess formation, bacterial clearance, and overall inflammatory responses in the skin. These data demonstrate the balance of LTB4-induced inflammation is critical for regulating optimal immune responses during infections. This work highlights the importance of investigating the role of inflammatory mediators in the settings of health and disease. Targeting LTB4/BLT1 has therapeutic potential to regulate inflammation during MRSA skin infection by enhancing immune responses in settings of vulnerability or decrease inflammation in diabetes.
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    Leukotriene B4 licenses inflammasome activation to enhance skin host defense
    (National Academy of Science, 2020-12-01) Guerta Salina, Ana Carolina; Brandt, Stephanie L.; Klopfenstein, Nathan; Blackman, Amondrea; Ribeiro Bazzano, Júlia Miranda; Sá-Nunes, Anderson; Byers-Glosson, Nicole; Brodskyn, Claudia; Machado Tavares, Natalia; Santos Da Silva, Icaro Bonyek; Medeiros, Alexandra I.; Serezani, C. Henrique; Microbiology and Immunology, School of Medicine
    The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1β and IL-18 in addition to inducing a type of inflammatory cell death termed "pyroptosis." Leukotriene B4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1β and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB4-mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1β-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense.
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    Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes
    (American Association for the Advancement of Science, 2015-01) Filgueiras, Luciano Ribeiro; Brandt, Stephanie L.; Wang, Soujuan; Wang, Zhuo; Morris, David L.; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Jancar, Sonia; Serezani, C. Henrique; Microbiology and Immunology, School of Medicine
    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.