PDn-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function

Pistorius, Kimberly; Souza, Patricia R.; Matteis, Roberta De; Austin-Williams, Shani; Primdahl, Karoline Gangestad; Vik, Anders; Mazzacuva, Francesca; Colas, Romain A.; Marques, Raquel M.; Hansen, Trond Vidar; Dalli, Jesmond

doi:10.1016/j.chembiol.2018.04.017

Cited by 48 publications

(59 citation statements)

References 44 publications

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“…Different macrophage subsets, for example, display distinct lipid mediator profiles with monocyte-derived-macrophages skewed towards a classic phenotype expressing higher amounts of pro-inflammatory eicosanoids, whereas cells with an alternatively activated phenotype display higher concentrations of pro-resolving mediators (23–25). This shift is also linked with a differential expression of both lipid mediator biosynthetic enzymes as well as the phosphorylation status of ALOX5 (23, 25, 26). In the present study we found a decrease in the number of leukocytes in the CSF.…”

Section: Discussionmentioning

confidence: 99%

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Colas

Nhat

Thuong

et al. 2019

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29Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, 30 characterized by a dysregulated immune response that frequently leads to 31 neurological injury and death despite the best available treatment. The mechanisms 32 driving the inflammatory response in TBM are not well understood. To gain insights 33 into these mechanisms we used a lipid mediator profiling approach to investigate the 34 regulation of a novel group of host protective mediators, termed specialized pro-35 resolving mediators (SPM), in the cerebrospinal fluid (CSF) of adults with TBM 36 enrolled into a randomised placebo-controlled trial of adjunctive aspirin treatment. 37We found distinct lipid mediator profiles with increasing disease severity, changes 38 that were linked with an upregulation of inflammatory eicosanoids in patients with 39 severe TBM and a decrease in the production of a number of 5-lipoxygenase 40 (ALOX5)-derived SPM. CSF pro-resolving mediator concentrations were also 41 associated with 80-day survival. In survivors, we found a significant increase in pro-42 resolving mediator concentrations, including the ALOX5-derived resolvin (Rv)T2, 43RvT4 and 15-epi-Lipoxin (LX)B4, compared to those who died. Aspirin administration 44 increased the ratio of pro-resolving to pro-inflammatory mediators decreasing the 45 concentrations of the prothrombic mediator TxA2, changes that were linked with early 46 reductions in brain infarcts and deaths. Together, these findings identify a CSF SPM 47 signature that is associated with disease severity and 80-day mortality in TBM. 48Furthermore, the therapeutic manipulation of the ratio between pro-resolving 49 mediators and pro-inflammatory/thrombogenic mediators in the CSF, by aspirin for 50 example, offers a novel treatment strategy to reduce the morbidity and mortality 51 caused by TBM. Authors Summary 54Infections of the brain and the meninges by Mycobacterium tuberculosis (M. tb) lead 55 to severe inflammation and are associated with poor outcomes. The mechanisms 56 leading to this disease remain poorly defined. Herein, we investigated how M. tb 57 infection regulates the concentrations of specialized pro-resolving mediators that are 58 central in controlling the body's ability to clear infections. In these investigations, we 59 found that disease survival was linked with increased concentrations of a number of 60 these protective molecules including resolvins and lipoxins. Treatment of M. tb-61 infected patients with aspirin decreased the production of the immunosuppressive 62 and thrombogenic mediator thromboxane A2 improving the balance between 63 protective and inflammatory molecules. Of note, these changes were linked with 64 reduced disease severity and improved survival. Therefore, the present findings 65 suggest a previously unappreciated role for pro-resolving mediators in TBM 66 pathogenesis.67 90 mediate the protective actions of several widely used therapeutics, including 91 atorvastatin, pravastatin and aspirin (7, 12, 13). 92We recently tested the hypot...

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Section: Discussionmentioning

confidence: 99%

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Colas

Nhat

Thuong

et al. 2019

Preprint

Self Cite

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“…34 Partial least square projection to latent structures discriminant analysis (PLS-DA) was performed using SIMCA 14.1 software (Umetrics, Umea, Sweden). Evaluation of loading plots was performed as previously described, 35 and variables with best discriminatory power (variable importance in projection ≥ 1) were highlighted in the Score plot.…”

Section: Cytokine Measurementmentioning

confidence: 99%

A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA

et al. 2020

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Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether the combination has superior beneficial effects on the outcome of asthmatic mice. Mice were sensitized with house dust mite (HDM) extract, and subsequently supplemented with either a combination of LCPUFAs or EPA alone in a recall asthma model. After the final HDM and LCPUFA administration, airway hyperresponsiveness (AHR), bronchoalveolar lavages, and lung histochemistry were examined. Lipid mediator profiles were determined by liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). The LCPUFA combination reduced AHR, eosinophilic inflammation, and inflammatory cytokines (IL-5, IFN-γ, and IL-6) in asthmatic mice, whereas EPA enhanced inflammation. The combination of LCPUFAs was more potent in downregulating EPAderived LTB 5 and LTC 5 and in supporting DHA-derived RvD1 and RvD4 (2.22-fold and 2.58-fold higher levels) than EPA alone. Ex vivo experiments showed that LTB 5 contributes to granulocytes' migration and M1-polarization in monocytes. Consequently, the LCPUFA combination ameliorated airway inflammation by inhibiting adverse effects of EPA and promoting pro-resolving effects supporting the lipid mediator-dependent resolution program.

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“…Many actions exerted by SPMs to limit infection have been described in non-CF cells isolated from human and mice macrophages, ( Chiang et al, 2012 ; Colas et al, 2016 ; Pierdomenico et al, 2017 ; Codagnone et al, 2018 ) ( Table 3 ). In addition, SPMs (PDn-3DPA, RvD1, and RvD2) stimulate macrophage differentiation from a pro-inflammatory (M1) to a pro-resolutive phenotype (M2) in non-CF models ( Dalli and Serhan, 2012 ; Recchiuti et al, 2014 ; Croasdell et al, 2015 ; Pistorius et al, 2018 ) and enhance the expression of surface receptors involved in the uptake of apoptotic cells ( Matte et al, 2019 ) ( Table 3 ). RvD2 also reduces polymicrobial sepsis severity in mice ( Spite et al, 2009 ) and MaR1 and RvD3 enhance E. coli phagocytosis by macrophages ( Colas et al, 2016 ) ( Table 3 ).…”

Section: Impact Of Spm S Demonstrated In Cf Modelsmentioning

confidence: 99%

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

2020

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Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients’ lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

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PDn-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function

Cited by 48 publications

References 44 publications

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

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