The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

Christofides, Anthos; Konstantinidou, Eirini; Jani, Chinmay; Boussiotis, Vassiliki A.

doi:10.1016/j.metabol.2020.154338

Cited by 325 publications

(234 citation statements)

References 186 publications

(221 reference statements)

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“…PPARs are nuclear receptor family of transcription factors activated by fatty acids and regulate lipid homeostasis [ 19 ]. PPARs have three isoforms, so-called PPARα, PPARβ/δ, and PPARγ, which are involved in fatty acid metabolism, lipid biosynthesis, and fatty acid oxidation [ 20 ]. Several natural lipophilic acids, including the enzymatic derivatives of linoleic acid and arachidonic acid metabolism by LOXs, such as eicosanoids, can bind to PPARγ as ligands [ 21 ] and prevent the inflammatory signaling [ [22] , [23] , [24] ].…”

Section: Resultsmentioning

confidence: 99%

Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

et al. 2021

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The molecular events that modulate the progression of monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia (WM) are mostly unknown. We implemented comparative proteomics and metabolomics analyses on patient serum samples to identify differentially expressed molecules crucial to the progression from IgM-MGUS to WM. Our data identified altered lipid metabolism as a discriminating factor between MGUS, WM, and matched normal controls. Levels of many fatty acids, including polyunsaturated fatty acids and dicarboxylic acids, were significantly downregulated in WM sera when compared to MGUS. These reductions were associated with diminished 15-LOX and PPAR protein expression and increased 5-LOX and GPX4 expression in WM versus MGUS patients’ samples. Furthermore, WM serum samples showed increased lipid peroxidation compared to MGUS. Treatment with IL-6 or TNFα, upstream regulators of differentially expressed proteins between MGUS and WM, increased lipid absorption and lipid peroxidation in WM cell lines. Knock-down of 15-LOX expression increased WM cell survival, an effect accompanied by increased 5-LOX and GPX4 expression. In summary, our data show that reduced fatty acid and lipid metabolite levels in the serum of the WM patients are associated with increased lipid peroxidation and that downregulation of 15-LOX increases the survival of WM cells. These data are highly significant in identifying the biomarkers of disease progression and designing targeted therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

et al. 2021

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“…Beside their effects on cell proliferation and differentiation, they are known activators of PPARγ [ 31 ]. Actually, peroxisome proliferator-activated receptors are known to induce the uptake and metabolism of fatty acids and to strongly modulate immune functions [ 32 ]. As fatty acid metabolism takes place in peroxisomes [ 33 ], the 5-HETE/15-HETE induced up-regulation of PEX16 ( Figure 4 ), a peroxisome biogenesis protein indicative for peroxisome proliferation [ 18 ], indicated that this treatment caused an increased demand for these organelles.…”

Section: Discussionmentioning

confidence: 99%

Eicosanoid Content in Fetal Calf Serum Accounts for Reproducibility Challenges in Cell Culture

et al. 2021

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Reproducibility issues regarding in vitro cell culture experiments are related to genetic fluctuations and batch-wise variations of biological materials such as fetal calf serum (FCS). Genome sequencing may control the former, while the latter may remain unrecognized. Using a U937 macrophage model for cell differentiation and inflammation, we investigated whether the formation of effector molecules was dependent on the FCS batch used for cultivation. High resolution mass spectrometry (HRMS) was used to identify FCS constituents and to explore their effects on cultured cells evaluating secreted cytokines, eicosanoids, and other inflammatory mediators. Remarkably, the FCS eicosanoid composition showed more batch-dependent variations than the protein composition. Efficient uptake of fatty acids from the medium by U937 macrophages and inflammation-induced release thereof was evidenced using C13-labelled arachidonic acid, highlighting rapid lipid metabolism. For functional testing, FCS batch-dependent nanomolar concentration differences of two selected eicosanoids, 5-HETE and 15-HETE, were balanced out by spiking. Culturing U937 cells at these defined conditions indeed resulted in significant proteome alterations indicating HETE-induced PPARγ activation, independently corroborated by HETE-induced formation of peroxisomes observed by high-resolution microscopy. In conclusion, the present data demonstrate that FCS-contained eicosanoids, subject to substantial batch-wise variation, may modulate cellular effector functions in cell culture experiments.

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“…Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors that regulate energy metabolism, and PPARγ is especially important for glucose lipid storage [ 36 ]. Paracrine signaling via the Wnt5α-β-catenin-PPAR-γ pathway in DCs can also establish a favorable immune context for tumor growth.…”

Section: Dendritic Cellsmentioning

confidence: 99%

Metabolism of Innate Immune Cells in Cancer

Talty

Olino

2021

Cancers

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Cancer cells possess specific metabolic requirements for their survival, proliferation, and progression. Within a shared microenvironment, immune cells depend on competing metabolic pathways for their development and effector function. As a result, local acidification, hypoxia, and nutrient depletion in the tumor microenvironment can alter the antitumor immune response and even promote resistance to immunotherapies such as immune checkpoint blockade and adoptive cell transfer. Although T cells are the primary effectors of the antitumor response, growing evidence demonstrates that innate immune cells are critical to successful tumor clearance. This review aims to summarize current research related to the innate immune system, metabolism, and cancer. We first discuss the specific metabolic requirements of innate immune cells for immune activation and suppression and conclude by highlighting ongoing clinical applications of these findings.

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The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

Cited by 325 publications

References 186 publications

Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

Eicosanoid Content in Fetal Calf Serum Accounts for Reproducibility Challenges in Cell Culture

Metabolism of Innate Immune Cells in Cancer

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