Leukotriene B4 modulation of murine dendritic cells affects adaptive immunity

Pires-Lapa, Marco Antonio; Koga, Marianna M.; Silva, Ildefonso; Filgueiras, Luciano Ribeiro; Jancar, Sônia

doi:10.1016/j.prostaglandins.2019.02.001

Cited by 6 publications

(8 citation statements)

References 28 publications

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“…Without LTB 4 , neutrophil recruitment to the site of infection would be impaired. Moreover, as LTB 4 also stimulates macrophages toward enhanced phagosomal degradation of microorganisms (28) and promotes dendritic cell activation of T-cell responses (113)(114)(115), both of these important mechanisms to coordinate early antimicrobial responses by host innate immune cells are likely impaired during Y. pestis infection. Inhibition of neutrophil degranulation and LTB 4 production likely contributes to Y. pestis subverting the innate immune response and maintaining a noninflammatory host environment early during infection.…”

Section: Discussionmentioning

confidence: 99%

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

et al. 2020

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Yersinia pestis causes a rapid, lethal disease referred to as plague. Y. pestis actively inhibits the innate immune system to generate a noninflammatory environment during early stages of infection to promote colonization. The ability of Y. pestis to create this early noninflammatory environment is in part due to the action of seven Yop effector proteins that are directly injected into host cells via a type 3 secretion system (T3SS). While each Yop effector interacts with specific host proteins to inhibit their function, several Yop effectors either target the same host protein or inhibit converging signaling pathways, leading to functional redundancy. Previous work established that Y. pestis uses the T3SS to inhibit neutrophil respiratory burst, phagocytosis, and release of inflammatory cytokines. Here, we show that Y. pestis also inhibits release of granules in a T3SS-dependent manner. Moreover, using a gain-of-function approach, we discovered previously hidden contributions of YpkA and YopJ to inhibition and that cooperative actions by multiple Yop effectors are required to effectively inhibit degranulation. Independent from degranulation, we also show that multiple Yop effectors can inhibit synthesis of leukotriene B4 (LTB4), a potent lipid mediator released by neutrophils early during infection to promote inflammation. Together, inhibition of these two arms of the neutrophil response likely contributes to the noninflammatory environment needed for Y. pestis colonization and proliferation.

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Section: Discussionmentioning

confidence: 99%

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

et al. 2020

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“…Presumably, a higher viral load would also increase the production of eicosanoids through activation of TLRs as described above, but it is also possible that eicosanoids directly regulate the activity of CD4+ cells. Both CD4+ and CD8+ cells express enzymes for arachidonic acid metabolism including COX1, COX2, 5-LOX, and PGG2 migration of macrophages and CD4+ cells into tissues including brain 32 . Indeed, elevated numbers of macrophages and T cells in brain parenchyma of PWH is a common finding 33 .…”

Section: Discussionmentioning

confidence: 99%

“… 30 LTB4 signaling through BLT1 promotes activation, cytokine production, chemotaxis, endothelial adhesion, and migration of macrophages and CD4 + cells into tissues including brain. 31 Indeed, the elevated numbers of macrophages and T cells in brain parenchyma of PWH is a common finding. 32 We also observed that ART did not substantially reduce circulating levels of eicosanoids in addition to a negative association with low nadir CD4.…”

Section: Discussionmentioning

confidence: 99%

Association of Plasma Eicosanoid Levels With Immune, Viral, and Cognitive Outcomes in People With HIV

et al. 2022

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Objective.To determine if plasma eicosanoid levels are associated with immune, viral, and cognitive outcomes in people with the human immunodeficiency virus (PWH).Methods.We measured 42 eicosanoids in a longitudinal study of 95 PWH and 25 demographically comparable uninfected participants. Routine clinical chemistry, virologic, immune markers and a neuropsychological test battery assessing seven cognitive domains was administered to all participants at two study visits over an average of 6.5 months.Results.Plasma eicosanoid concentrations were elevated in PWH (n=95) compared to seronegative controls (n=25) (100% prediction power at 5% FDR, α=0.0531) and in PWH were negatively associated with lower current and nadir CD4 lymphocyte counts. Higher levels of eicosanoids were associated with impairments in working memory, verbal fluency, and executive function. Higher plasma viral load was associated with elevated pro-inflammatory eicosanoids (24% prediction power at 5% FDR, and 42.4% prediction power at 10% FDR, α=0.10). Longitudinal analyses showed that eicosanoid levels were correlated with viral load and with plasma creatinine. Despite associations of eicosanoids with viral loads, elevated plasma eicosanoids were similar in virally suppressed and not-fully suppressed PWH.Conclusions.These data show that HIV infection is associated with a robust production of eicosanoids that is not substantially reduced by antiretroviral therapy (ART). The sustained elevation of these oxylipins in PWH despite ART may contribute to an accelerated aging phenotype that includes earlier than expected brain and peripheral organ damage.

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“…36 LTB4 affects dendritic cells (DCs) and regulates the type of adaptive immune response, and LTB4-stimulated DCs induce Treg proliferation and increase the expression of the Th2 cytokine IL-13, as well as the transcription factor genes Gata3 and Foxp3. 37 BLT-1 is an LTB4 high-affinity receptor, and BLT1 is highly expressed in activated Tregs, and BLT1 plays a role in the resolution of experimental acute lung injury (ALI) by mediating Treg recruitment to the alveoli. 38 These studies show that montelukast plays different roles in the development and differentiation of T cells in various disease models, and the specific mechanisms need to be explored.…”

Section: Discussionmentioning

confidence: 99%

Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model

Han

Zhang

et al. 2021

Immunology

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Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4 + T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.

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Leukotriene B4 modulation of murine dendritic cells affects adaptive immunity

Cited by 6 publications

References 28 publications

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

Association of Plasma Eicosanoid Levels With Immune, Viral, and Cognitive Outcomes in People With HIV

Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model

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