Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses

Nath, Anu S.; Parsons, Brendon; Makdissi, Stephanie; Chilvers, Rebecca L.; Mu, Yizhu; Weaver, Ceileigh M.; Euodia, Irene; Fitze, Katherine A.; Long, Juyang; Scur, Michal; Mackenzie, Duncan P.; Makrigiannis, Andrew P.; Pichaud, Nicolas; Boudreau, Luc H.; Simmonds, Andrew; Webber, Christine A.; Hammon, Yannick; Rachubinski, Richard A.; Cara, Francesca Di

doi:10.1016/j.celrep.2022.110433

Cited by 13 publications

(12 citation statements)

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“…The current study showed the importance of peroxisome-mediated lipid metabolism in MCs and indicates that proper regulation of FFAs modulates MCs activation and cytokine production. Our work and recent studies ( Eguchi et al, 1979 ; Singh et al, 2004 ; Di Cara et al, 2017 , 2019 ; Vijayan et al, 2017 ; Nath et al, 2022 ) revealing peroxisome involvement in immune processes, provide a new avenue for therapeutic targeting. Such interventions, focused on MCs, may allow local modulation of immune and inflammatory events in specific mast cell-rich tissues such as the skin, airways or tumour microenvironment.…”

Section: Discussionsupporting

confidence: 55%

“…Different studies have shown that the metabolism of fatty acids (FAs) is a major source of biological lipids that form cell membranes and regulate inflammatory functions ( Dowds et al, 2014 ; Hubler and Kennedy, 2016 ; Nath et al, 2022 ; O'Neill et al, 2016 ; Puertollano et al, 2001 ; Sadik and Luster, 2012 ). Peroxisomes contribute to the homeostasis of FAs in the cell ( Wanders and Waterham, 2006 ; Lodhi and Semenkovich, 2014 ) and we probed whether free fatty acids (FFAs) are altered in MCs in absence of peroxisomes, affecting cytokine release.…”

Section: Resultsmentioning

confidence: 99%

“…To explore the link between FFAs and MCs activation, we used Niacin a vitamin B3 shown to reduce FFAs in plasma, macrophages and adipocytes by inducing anti-lipolytic effects ( Tunaru et al, 2003 ; Nath et al, 2022 ). Human MCs have been shown to respond to niacin treatment by prostaglandin D2 (PGD 2 ) production ( Papaliodis et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

“…Peroxisomes have been recognized as organelles of immunity with central immunometabolic and signaling functions to regulate immune response to pathogens ( Sychev et al, 2017 ; Xu et al, 2017 ; Cook et al, 2019 ; Merkling et al, 2019 ). We have previously shown the central role of peroxisome in macrophage-mediated host defense ( Di Cara et al, 2017 ; Nath et al, 2022 ). The present study aimed to define the role of peroxisome metabolism in the context of TLR and IgE-mediated activation of MCs.…”

Section: Discussionmentioning

confidence: 99%

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Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation

Meghnem

Leong

Pinelli

et al. 2022

Front. Cell Dev. Biol.

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Mast cells are specialized, tissue resident, immune effector cells able to respond to a wide range of stimuli. MCs are involved in the regulation of a variety of physiological functions, including vasodilation, angiogenesis and pathogen elimination. In addition, MCs recruit and regulate the functions of many immune cells such as dendritic cells, macrophages, T cells, B cells and eosinophils through their selective production of multiple cytokines and chemokines. MCs generate and release multi-potent molecules, such as histamine, proteases, prostanoids, leukotrienes, heparin, and many cytokines, chemokines, and growth factors through both degranulation dependent and independent pathways. Recent studies suggested that metabolic shifts dictate the activation and granule content secretion by MCs, however the metabolic signaling promoting these events is at its infancy. Lipid metabolism is recognized as a pivotal immunometabolic regulator during immune cell activation. Peroxisomes are organelles found across all eukaryotes, with a pivotal role in lipid metabolism and the detoxification of reactive oxygen species. Peroxisomes are one of the emerging axes in immunometabolism. Here we identified the peroxisome as an essential player in MCs activation. We determined that lack of functional peroxisomes in murine MCs causes a significant reduction of interleukin-6, Tumor necrosis factor and InterleukinL-13 following immunoglobulin IgE-mediated and Toll like receptor 2 and 4 activation compared to the Wild type (WT) BMMCs. We linked these defects in cytokine release to defects in free fatty acids homeostasis. In conclusion, our study identified the importance of peroxisomal fatty acids homeostasis in regulating mast cell-mediated immune functions.

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation

Meghnem

Leong

Pinelli

et al. 2022

Front. Cell Dev. Biol.

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“…Our study also extends the current focus of peroxisome-mediated lipid changes in cancer cells to exploring the contribution of peroxisomes to tumorigenesis in the tumour microenvironment (i.e. immunity and inflammation 52,69,70 ), potentially opening up new therapeutic avenues to fight tumour cell proliferation by targeting peroxisome-related processes. Collectively, our findings make a new contribution to the study of altered lipid metabolism in PCa and reveals DECR2 as a major modulator of cell cycle progression and lipid metabolism, and an exciting novel candidate for therapeutic targeting.…”

Section: Peroxisomal β-Oxidation (Perfao) Is An Understudied Aspect O...mentioning

confidence: 58%

Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer

Mah

Nguyen

Niijima

et al. 2022

Preprint

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Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.

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Self‐Activating Phosphorus‐Rich Substrate Import Enzyme Catalytic Domains for Bone Regeneration

Zhao,

Chen,

Tang

et al. 2024

Adv Funct Materials

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Enzymes play a key role in natural mineralization, but their function is disabling in bone metabolism when patients suffer severe degenerations like hypophosphatasia. To regulate bone homeostasis, a self‐activating phosphorus‐rich system is proposed on calcium glycerophosphate (CaGP) modified polyurethane (PU) fibrous substrate, wherein ample enzyme catalytic domains are imported with intestinal alkaline phosphatase (IALP) chelating and activating by calcium in situ that is testified by chemical potential evaluation. Therefore, Ca‐bonding IALP catalyzes organophosphate to phosphate locally to achieve a calcified symbiotic state, regulating mineralization and accelerating osteoinduction in vitro and in vivo. The self‐activating enzyme system promotes early osteogenic differentiation and angiogenesis, resulting in rapid healing of cranial defect with a “long‐tail” effect compared to an enzyme‐assisted system. Transcriptomic and metabolomic analyses demonstrate positive associations with neovascularization and calcium/phosphorus metabolism, specifically upregulated glycerophospholipids and calcium ions in favor of osteogenic differentiation under cytokine‐free conditions. These results provide a potential enzyme‐activating therapy in bone homeostasis and regeneration.

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Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses

Cited by 13 publications

References 132 publications

Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation

Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation

Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer

Self‐Activating Phosphorus‐Rich Substrate Import Enzyme Catalytic Domains for Bone Regeneration

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