Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB4 reduction but not PGE2 increment

Sorgi, Carlos Artério; Soares, Elyara Maria; Rosada, Rogério Silva; Bitencourt, Claudia S.; Zoccal, Karina Furlani; Pereira, Priscilla Aparecida Tártari; Fontanari, Caroline; Brandão, I. T.; Masson, Ana Paula; Ramos, Simone G.; Silva, Célio Lopes; Frantz, Fabiani Gai; Faccioli, Lúcia Helena

doi:10.1016/j.bbadis.2019.165574

Cited by 32 publications

(44 citation statements)

References 64 publications

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“…Several studies have emphasized the role of eicosanoids and lipid mediators in TB pathogenesis (30)(31)(32). We hypothesized that the AA-derived metabolites PGE2, LXA4, and LTB4 reflects the ongoing inflammation and resolution processes orchestrated by eicosanoids in TB.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease

et al. 2020

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Eicosanoids modulate both innate and adaptive immune responses in Mycobacterium tuberculosis (Mtb) infection and have been suggested as possible Host Directed Therapy (HDT) targets, but more knowledge of eicosanoid dynamics in Mtb infection is required. We investigated the levels and ratios of eicosanoid mediators and their cellular sources, monocyte subsets and CD4 T cells in Tuberculosis (TB) patients with various clinical states of Mtb infection. Patients consenting to prospective enrolment in a TB quality registry and biorepository, 16 with pulmonary TB (before and at-end-of treatment), 14 with extrapulmonary TB and 17 latently infected (LTBI) were included. Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were measured by enzyme-linked immunosorbent assay. Monocyte subsets and CD4 T cells and their expression of Cyclooxygenase-2 (COX-2), Prostaglandin receptor EP2 (EP2), and 5-Lipoxygenase (5-LOX) were analyzed by flow cytometry with and without Purified Protein Derivate (PPD)-stimulation. Pulmonary TB patients had elevated levels of the anti-inflammatory mediator LXA4 at diagnosis compared to LTBI (p < 0.01), while levels of PGE2 and LTB4 showed no difference between clinical states of Mtb infection. LTB4 was the only mediator to be reduced upon treatment (p < 0.05), along with the ratio LTB4/LXA4 (p < 0.01). Pulmonary TB patients had higher levels of total monocytes at diagnosis compared to end-of-treatment and LTBI (both p < 0.05), and a relative increase in the classical monocyte subset. All monocyte subsets had low basal expression of COX-2 and 5-LOX, which were markedly increased upon PPD stimulation. By contrast, the expression of EP2 was reduced upon stimulation. CD4 T cells expressed low basal COX-2 activity that increased modestly upon stimulation, whereas their basal expression of 5-LOX was considerable. In conclusion, the level of eicosanoids in plasma seem to vary between clinical states of Mtb infection. Mediators in the eicosanoid system are present in monocytes and CD4 T cells. The expression of eicosanoids in monocytes are responsive to mycobacterial stimulation independent of Mtb disease state, but subsets are heterogeneous with regard to eicosanoid-mediator expression. Further exploration of eicosanoid mediators as targets for HDT in TB are warranted.

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Section: Discussionmentioning

confidence: 99%

Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease

et al. 2020

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“…Thus, the inhibitory or stimulating effect of PGE2 might vary during the acute and chronic stages of TB infection. Moreover, Sorgi et al demonstrated that COX-2 inhibition signi cantly reduced PGE2 levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb, reinforcing the notion that optimal PGE2 levels are required for effective modulation of the immune response against Mtb infection 47 . Thus, during the design of new personalized treatments focused on the regulation of the levels of host eicosanoids, these various consequences will have to be considered.…”

Section: Discussionmentioning

confidence: 91%

PGE2 Displays Immunosuppressive Effects During Human Active Tuberculosis

Pellegrini

Martin

Morelli

et al. 2021

Preprint

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Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced lymphoproliferation, the production of proinflammatory cytokines, and the surface expression of several immunological receptors. On the other hand, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb, emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.

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“…Apart from the important functions of LMs in the inflammatory response in TB, they also influence TB pathogenesis (41,42). As such, LMs play a fundamental role in determining the fate of macrophages and their phagocytic ability, as well as immune cell recruitment (44,45).…”

Section: Lipid Mediators In Tuberculosismentioning

confidence: 99%

“…The functions of individual LMs in TB remain controversial but more recent research suggests that the balance and timing of the production of specific LMs during the TB disease course are essential for good treatment outcomes (12,41,44,46). For example, the essential action of PGE 2 in the innate immune response of human TB and how a balance in PGE 2 /LTB 4 prevents severe inflammation and immunopathology (44,47). Additionally, the AA-derived LXA 4 has been positively correlated with inflammation and bacterial burden in TB patients (41).…”

Section: Lipid Mediators In Tuberculosismentioning

confidence: 99%

“…Similarly, diclofenac treatment has been shown to reduce lung lesions and bacillary load and increase survival in murine models (64,65). The new generation NSAID celecoxib also selectively inhibits COX-2 but has fewer side effects (44). It can increase the sensitivity of bacteria to antibacterial treatment and reverse MDR-TB (66,67).…”

Section: Preclinical Trials On Cyclooxygenase-and Lipoxygenase-modulamentioning

confidence: 99%

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The Manipulation of the Lipid Mediator Metabolism as Adjunct Host-Directed Therapy in Tuberculosis

et al. 2021

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Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients.

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Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB4 reduction but not PGE2 increment

Cited by 32 publications

References 64 publications

Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease

Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease

PGE2 Displays Immunosuppressive Effects During Human Active Tuberculosis

The Manipulation of the Lipid Mediator Metabolism as Adjunct Host-Directed Therapy in Tuberculosis

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