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Excessive localized leukotriene B4 levels dictate poor skin host defense in diabetic mice.
Brandt SL, Wang S, Dejani NN, Klopfenstein N, Winfree S, Filgueiras L, McCarthy BP, Territo PR, Serezani CH
(2018) JCI Insight 3:
MeSH Terms: Abscess, Animals, Bacterial Load, Cell Movement, Chemokines, Cytokines, Diabetes Mellitus, Experimental, Female, Inflammation, Leukotriene B4, Macrophages, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils, Receptors, Leukotriene B4, Signal Transduction, Skin, Staphylococcal Skin Infections
Show Abstract · Added March 18, 2020
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.
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Macrophage-derived LTB4 promotes abscess formation and clearance of Staphylococcus aureus skin infection in mice.
Brandt SL, Klopfenstein N, Wang S, Winfree S, McCarthy BP, Territo PR, Miller L, Serezani CH
(2018) PLoS Pathog 14: e1007244
MeSH Terms: Abscess, Animals, Arachidonate 5-Lipoxygenase, Bacterial Load, Cells, Cultured, Female, Leukotriene B4, Macrophages, Male, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Leukotriene B4, Staphylococcal Skin Infections
Show Abstract · Added March 18, 2020
The early events that shape the innate immune response to restrain pathogens during skin infections remain elusive. Methicillin-resistant Staphylococcus aureus (MRSA) infection engages phagocyte chemotaxis, abscess formation, and microbial clearance. Upon infection, neutrophils and monocytes find a gradient of chemoattractants that influence both phagocyte direction and microbial clearance. The bioactive lipid leukotriene B4 (LTB4) is quickly (seconds to minutes) produced by 5-lipoxygenase (5-LO) and signals through the G protein-coupled receptors LTB4R1 (BLT1) or BLT2 in phagocytes and structural cells. Although it is known that LTB4 enhances antimicrobial effector functions in vitro, whether prompt LTB4 production is required for bacterial clearance and development of an inflammatory milieu necessary for abscess formation to restrain pathogen dissemination is unknown. We found that LTB4 is produced in areas near the abscess and BLT1 deficient mice are unable to form an abscess, elicit neutrophil chemotaxis, generation of neutrophil and monocyte chemokines, as well as reactive oxygen species-dependent bacterial clearance. We also found that an ointment containing LTB4 synergizes with antibiotics to eliminate MRSA potently. Here, we uncovered a heretofore unknown role of macrophage-derived LTB4 in orchestrating the chemoattractant gradient required for abscess formation, while amplifying antimicrobial effector functions.
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Too much of a good thing: How modulating LTB actions restore host defense in homeostasis or disease.
Brandt SL, Serezani CH
(2017) Semin Immunol 33: 37-43
MeSH Terms: Animals, Cell Movement, Homeostasis, Humans, Immunity, Innate, Immunomodulation, Inflammation, Leukotriene B4, Neutrophils, Phagocytosis
Show Abstract · Added March 18, 2020
The ability to regulate inflammatory pathways and host defense mechanisms is critical for maintaining homeostasis and responding to infections and tissue injury. While unbalanced inflammation is detrimental to the host; inadequate inflammation might not provide effective signals required to eliminate pathogens. On the other hand, aberrant inflammation could result in organ damage and impair host defense. The lipid mediator leukotriene B (LTB) is a potent neutrophil chemoattractant and recently, its role as a dominant molecule that amplifies many arms of phagocyte antimicrobial effector function has been unveiled. However, excessive LTB production contributes to disease severity in chronic inflammatory diseases such as diabetes and arthritis, which could potentially be involved in poor host defense in these groups of patients. In this review we discuss the cellular and molecular programs elicited during LTB production and actions on innate immunity host defense mechanisms as well as potential therapeutic strategies to improve host defense.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
(2016) Nat Commun 7: 10760
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Blotting, Western, Carrier Proteins, Celecoxib, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclooxygenase Inhibitors, Dinoprostone, In Vitro Techniques, Indoles, Indomethacin, Inflammasomes, Interleukin-1beta, Leukotriene B4, Lipoxygenase Inhibitors, Macrophages, Macrophages, Peritoneal, Mice, Mice, Knockout, NF-kappa B, NLR Family, Pyrin Domain-Containing 3 Protein, Phosphoproteins, Prostaglandin Antagonists, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype, Reverse Transcriptase Polymerase Chain Reaction, Scorpion Stings, Scorpion Venoms, Scorpions, Xanthones
Show Abstract · Added May 4, 2017
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis.
Ribeiro LR, Loures FV, de Araújo EF, Feriotti C, Costa TA, Serezani CH, Jancar S, Calich VL
(2015) Mediators Inflamm 2015: 852574
MeSH Terms: Acetates, Animals, Arachidonate 5-Lipoxygenase, Dinoprostone, Inflammation Mediators, Leukotriene Antagonists, Leukotriene C4, Lipoxins, Macrophages, Alveolar, Male, Mice, Mice, 129 Strain, Mice, Inbred A, Mice, Knockout, Paracoccidioides, Paracoccidioidomycosis, Quinolines, Receptors, Leukotriene, Receptors, Pattern Recognition
Show Abstract · Added May 4, 2017
Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
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Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes.
Filgueiras LR, Brandt SL, Wang S, Wang Z, Morris DL, Evans-Molina C, Mirmira RG, Jancar S, Serezani CH
(2015) Sci Signal 8: ra10
MeSH Terms: Analysis of Variance, Animals, Arachidonate 5-Lipoxygenase, Chromatin Immunoprecipitation, Cytokines, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Immunoblotting, Inflammation, Inflammation Mediators, Insulin, Leukotriene B4, Macrophages, Mice, Mice, Knockout, Myeloid Differentiation Factor 88, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, Sepsis
Show Abstract · Added May 4, 2017
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.
Copyright © 2015, American Association for the Advancement of Science.
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21 MeSH Terms
Use of leukotriene receptor antagonists are associated with a similar risk of asthma exacerbations as inhaled corticosteroids.
Wu AC, Li L, Fung V, Kharbanda EO, Larkin EK, Vollmer WM, Butler MG, Miroshnik I, Rusinak D, Davis RL, Hartert T, Weiss ST, Lieu TA
(2014) J Allergy Clin Immunol Pract 2: 607-13
MeSH Terms: Administration, Inhalation, Adolescent, Adrenal Cortex Hormones, Adrenergic beta-Agonists, Anti-Asthmatic Agents, Asthma, Child, Child, Preschool, Emergency Service, Hospital, Female, Hospitalization, Humans, Leukotriene Antagonists, Male, Retrospective Studies, Rhinitis, Allergic, Risk, Treatment Outcome, United States
Show Abstract · Added January 20, 2015
BACKGROUND - Based on results of clinical trials, inhaled corticosteroids (ICS) are the most-effective controller medications for preventing asthma-related exacerbations, yet few studies in real-life populations have evaluated the comparative effectiveness of ICS.
OBJECTIVE - To determine the likelihood of asthma exacerbations among children with asthma after initiation of controller medications: ICS, leukotriene antagonists (LTRA), and ICS-long-acting β-agonist (LABA) combination therapy.
METHODS - This was a retrospective cohort study of subjects who were part of the Population-Based Effectiveness in Asthma and Lung Diseases Network. We conducted Cox regression analyses by adjusting for baseline covariates, adherence by using proportion of days covered, and high-dimensional propensity scores. The main outcome measurements were emergency department visits, hospitalizations, or oral corticosteroid use.
RESULTS - Our population included 15,567 health plan subjects and 10,624 TennCare Medicaid subjects with uncontrolled asthma. Overall adherence to controller medications was low, with no more than 50% of the subjects refilling the medication after the initial fill. For subjects with allergic rhinitis, the subjects in TennCare Medicaid treated with LTRAs were less likely to experience ED visits (hazard ratio 0.44 [95% CI, 0.21-0.93]) compared with the subjects treated with ICS. For all other groups, the subjects treated with LTRA or ICS-LABA were just as likely to experience ED visits or hospitalizations, or need oral corticosteroids as the subjects treated with ICS.
CONCLUSION - Risks of asthma-related exacerbations did not differ between children who initiated LTRA and ICS. These findings may be explainable by LTRA, which has similar effectiveness as ICS in real-life usage by residual confounding by indication or other unmeasured factors.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Essential role of leukotriene B4 on Leishmania (Viannia) braziliensis killing by human macrophages.
Morato CI, da Silva IA, Borges AF, Dorta ML, Oliveira MA, Jancar S, Serezani CH, Ribeiro-Dias F
(2014) Microbes Infect 16: 945-53
MeSH Terms: Cell Survival, Cells, Cultured, Host-Pathogen Interactions, Humans, Leishmania braziliensis, Leukotriene B4, Macrophages, Reactive Oxygen Species, Receptors, Leukotriene B4
Show Abstract · Added May 4, 2017
Although Leishmania (Viannia) braziliensis is the most prevalent species that cause American tegumentary leishmaniasis (ATL), the immune response against this parasite has been poorly investigated. Upon activation, macrophages produce a series of pro-inflammatory molecules, including the lipid mediator leukotriene B4 (LTB4). LTB4 has been shown to enhance several macrophage functions, but its role in human macrophages is less known. Here, we investigated the role of LTB4 on human monocyte-derived macrophages infected with human isolate of L. (V.) braziliensis (IMG3). It was found that human macrophages produce LTB4 upon infection with Leishmania, which by autocrine or paracrine activation of its high affinity receptor BLT1, potentiates macrophage leishmanicidal activity. This LTB4 effect is mediated by increased secretion of reactive oxygen species (ROS). Moreover, Leishmania infection decreased the expression of BLT1, leading to the speculation that this could represent a parasite escape mechanism to establish a chronic inflammatory infection. Therefore, our data suggest that LTB4 could be used in therapeutic strategies to control Leishmania infection.
Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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9 MeSH Terms
Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation.
Wang Z, Filgueiras LR, Wang S, Serezani AP, Peters-Golden M, Jancar S, Serezani CH
(2014) J Immunol 192: 2349-56
MeSH Terms: Animals, Female, GTP-Binding Protein alpha Subunits, Gene Expression Regulation, Inflammation, Leukotriene B4, Macrophage Activation, Macrophages, Peritoneal, Mice, Mice, Knockout, MicroRNAs, Myeloid Differentiation Factor 88, Receptors, Leukotriene B4, Signal Transduction, Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling Proteins
Show Abstract · Added May 4, 2017
MicroRNAs are known to control TLR activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. In this study, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Gαi signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to activating protein-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both wild type and LT-deficient macrophages. To our knowledge, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs that regulate MyD88-dependent activation of macrophages.
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16 MeSH Terms
The leukotriene B₄/BLT₁ axis is a key determinant in susceptibility and resistance to histoplasmosis.
Secatto A, Soares EM, Locachevic GA, Assis PA, Paula-Silva FW, Serezani CH, de Medeiros AI, Faccioli LH
(2014) PLoS One 9: e85083
MeSH Terms: Animals, Arachidonate 5-Lipoxygenase, Disease Susceptibility, Enzyme Inhibitors, Gene Expression, Histoplasma, Histoplasmosis, Host Specificity, Host-Pathogen Interactions, Leukotriene B4, Lung, Macrophages, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Phagocytosis, Receptors, Leukotriene B4, Rodent Diseases, Signal Transduction, Spleen
Show Abstract · Added May 4, 2017
The bioactive lipid mediator leukotriene B4 (LTB4) greatly enhances phagocyte antimicrobial functions against a myriad of pathogens. In murine histoplasmosis, inhibition of the LT-generating enzyme 5-lypoxigenase (5-LO) increases the susceptibility of the host to infection. In this study, we investigated whether murine resistance or susceptibility to Histoplasma capsulatum infection is associated with leukotriene production and an enhancement of in vivo and/or in vitro antimicrobial effector function. We show that susceptible C57BL/6 mice exhibit a higher fungal burden in the lung and spleen, increased mortality, lower expression levels of 5-LO and leukotriene B4 receptor 1 (BLT1) and decreased LTB4 production compared to the resistant 129/Sv mice. Moreover, we demonstrate that endogenous and exogenous LTs are required for the optimal phagocytosis of H. capsulatum by macrophages from both murine strains, although C57BL/6 macrophages are more sensitive to the effects of LTB4 than 129/Sv macrophages. Therefore, our results provide novel evidence that LTB4 production and BLT1 signaling are required for a histoplasmosis-resistant phenotype.
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20 MeSH Terms