Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model

Pedruzzi, Gabriele; Das, Phonindra Nath; Rao, Kanury V. S.; Chatterjee, Samrat

doi:10.1016/j.jtbi.2015.10.025

Cited by 17 publications

(12 citation statements)

References 33 publications

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“…The balance between the lipid mediators LXA4 and LTB4 represents at least one of the factors that dictate susceptibility or protection. The disturbance of the 5-LO-dependent fine equilibrium of LTs and LXs could compromise the homeostasis of LXA4 and LTB4, leading to M. tb survival and dissemination (Herb et al, 2008;Tobin et al, 2012;Dietzold et al, 2015;Pedruzzi et al, 2016;Mishra et al, 2018). Consistently, our study has shown that Rv1768 induces 5-LO expression, consequently promoting LXA4 expression and inhibiting LTB4 expression.…”

Section: Discussionsupporting

confidence: 83%

PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism

et al. 2020

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Mycobacterium tuberculosis (M. tb) evades the surveillance of immune responses for survival in macrophages. However, the precise mechanism and toxins/proteins encoded by M. tb involved in the bacterial escape remain elusive. The function of Rv1768 protein (also referred to as PE_PGRS31, belonging to the PE_PGRS family) encoded by the region of deletion 14 (RD-14) in the virulent M. tb H37Rv strain has not, to the best of our knowledge, been reported previously. Here, we found that Rv1768 remarkably promotes bacterial survival in macrophages. Compared to wild type (WT) H37Rv, the Rv1768 deficient strain (H37Rv 1768) showed significantly decreased colony-forming units in the lungs, spleen, and liver of the murine M. tb infection model. The bacterial burdens of WT H37Rv in WT macrophages and C57BL/6 mice were significantly higher than those in S100A9 deficiency cells and mice, but there were no significant differences for H37Rv Rv1768. Rv1768 binds S100A9 with the proline-glutamic acid domain (PE domain) and blocks the interaction between S100A9 and Toll-like receptor 4 (TLR4), and suppresses TLR4-myeloid differentiation factor 88-nuclear factor-kappa B (NF-κB)-tumor necrosis factor α (TNF-α) signaling in macrophages. Interestingly, Rv1768 binding to S100A9 also disturbs the metabolism of arachidonic acid by activating 5-lipoxygenase, increasing lipotoxin A4, and down-regulating cyclooxygenase-2 and prostaglandin E2 expression, thus, promoting mycobacterial survival. Our results revealed that M. tb Rv1768 promotes mycobacterial survival in macrophages by regulating NF-κB-TNF-α signaling and arachidonic acid metabolism via S100A9. Disturbing the interaction between Rv1768 and S100A9 may be a potential therapeutic target for tuberculosis.

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Section: Discussionsupporting

confidence: 83%

PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism

et al. 2020

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“…Additionally, the spatial and temporal aspects of lipid mediator metabolism and receptor expression, along with the complementary or opposing activities of multiple lipid mediators must be addressed to fully elucidate the role lipid mediators play in leprosy. Mathematical models, as performed for M. tuberculosis infection ( 150 ), may be important to elucidate the influence PUFA-derived lipid mediator complexity in disease outcomes that might occur in individuals infected with M. leprae . It is also important to highlight that lipid mediators not identified or targeted in previous metabolomics studies on leprosy, may also contribute to immuno-pathogenesis.…”

Section: Summation and Conclusionmentioning

confidence: 99%

Host Lipid Mediators in Leprosy: The Hypothesized Contributions to Pathogenesis

Silva

Belisle

2018

Front. Immunol.

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The spectrum of clinical forms observed in leprosy and its pathogenesis are dictated by the host’s immune response against Mycobacterium leprae, the etiological agent of leprosy. Previous results, based on metabolomics studies, demonstrated a strong relationship between clinical manifestations of leprosy and alterations in the metabolism of ω3 and ω6 polyunsaturated fatty acids (PUFAs), and the diverse set of lipid mediators derived from PUFAs. PUFA-derived lipid mediators provide multiple functions during acute inflammation, and some lipid mediators are able to induce both pro- and anti-inflammatory responses as determined by the cell surface receptors being expressed, as well as the cell type expressing the receptors. However, little is known about how these compounds influence cellular immune activities during chronic granulomatous infectious diseases, such as leprosy. Current evidence suggests that specialized pro-resolving lipid mediators (SPMs) are involved in the down-modulation of the innate and adaptive immune response against M. leprae and that alteration in the homeostasis of pro-inflammatory lipid mediators versus SPMs is associated with dramatic shifts in the pathogenesis of leprosy. In this review, we discuss the possible consequences and present new hypotheses for the involvement of ω3 and ω6 PUFA metabolism in the pathogenesis of leprosy. A specific emphasis is placed on developing models of lipid mediator interactions with the innate and adaptive immune responses and the influence of these interactions on the outcome of leprosy.

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“…Thus, suppression of the excessive NO production is a new therapeutic strategy for chronic inflammatory diseases [49]. Another inflammatory mediator, PGE2, is synthesized by cyclooxygenase 2 (COX2) and also participates in many inflammatory diseases (e.g., TB) [52]. Here, we demonstrated that Mtb-induced NO production, as well as iNOS and COX2, was dramatically restrained by MCL treatment.…”

Section: Discussionmentioning

confidence: 81%

MCL Plays an Anti-Inflammatory Role inMycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

Zhang

Jiang

et al. 2017

Mediators of Inflammation

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Mycobacterium tuberculosis (Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1β and TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

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Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model

Cited by 17 publications

References 33 publications

PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism

PE_PGRS31-S100A9 Interaction Promotes Mycobacterial Survival in Macrophages Through the Regulation of NF-κB-TNF-α Signaling and Arachidonic Acid Metabolism

Host Lipid Mediators in Leprosy: The Hypothesized Contributions to Pathogenesis

MCL Plays an Anti-Inflammatory Role inMycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

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