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

Dihia Meghnem; Edwin Leong; Marinella Pinelli; Jean S. Marshall; Francesca Di Cara

doi:10.3389/fcell.2022.856243

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

Dihia Meghnem, Edwin Leong, Marinella Pinelli, Jean S. Marshall, Francesca Di Cara

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

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.

Original language	English
Article number	856243
Journal	Frontiers in Cell and Developmental Biology
Volume	10
DOIs	https://doi.org/10.3389/fcell.2022.856243
Publication status	Published - May 13 2022

Bibliographical note

Funding Information:
The Pex2 Mutant Mouse Strain used was 129S6.129-Pex2 /Mmmh(Null allele) () and was obtained from the Mutant Mouse Resource and Research Centre (MMRRC) supported by the NIH. The mice used for this experiment were Pex2 , Pex2 , Pex2 . Homozygous null mutant strains showed no Pex2 transcript and protein. Homozygous mutants in this congenic strain show variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygotes survive to birth but are hypotonic, do not feed and die on the day of birth. Homozygous mutants that survive in the postnatal period are obtained by mating congenic 129S6.129-Pex2 +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 +/- hybrids (designated Sw129) are then intercrossed to obtain Sw129-Pxmp3 −/− (indicated in the text as Pex2 ) mice. tm1Plf +/+ −/− +/− tm1Plf tm1Plf tm1Plf −/−

Funding Information:
This work was funded by a Discovery Grant from Natural Sciences and Engineering Research Council of Canada (NSERC) to FD, a Canada Foundation for Innovation (CFI) JELF equipment grant to FD, a Dalhousie Medical Research Foundation start-up fund to FD a Canadian Institute of Health Research project grant to JM. DM is supported by Dr. David H. Hubel Postdoctoral Fellowship funded by the Dalhousie Medical Research Foundation.

Publisher Copyright:
Copyright © 2022 Meghnem, Leong, Pinelli, Marshall and Di Cara.

ASJC Scopus Subject Areas

Developmental Biology
Cell Biology

PubMed: MeSH publication types

Journal Article

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10.3389/fcell.2022.856243

Cite this

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

abstract = "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.",

author = "Dihia Meghnem and Edwin Leong and Marinella Pinelli and Marshall, {Jean S.} and {Di Cara}, Francesca",

note = "Funding Information: The Pex2 Mutant Mouse Strain used was 129S6.129-Pex2 /Mmmh(Null allele) () and was obtained from the Mutant Mouse Resource and Research Centre (MMRRC) supported by the NIH. The mice used for this experiment were Pex2 , Pex2 , Pex2 . Homozygous null mutant strains showed no Pex2 transcript and protein. Homozygous mutants in this congenic strain show variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygotes survive to birth but are hypotonic, do not feed and die on the day of birth. Homozygous mutants that survive in the postnatal period are obtained by mating congenic 129S6.129-Pex2 +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 +/- hybrids (designated Sw129) are then intercrossed to obtain Sw129-Pxmp3 −/− (indicated in the text as Pex2 ) mice. tm1Plf +/+ −/− +/− tm1Plf tm1Plf tm1Plf −/− Funding Information: This work was funded by a Discovery Grant from Natural Sciences and Engineering Research Council of Canada (NSERC) to FD, a Canada Foundation for Innovation (CFI) JELF equipment grant to FD, a Dalhousie Medical Research Foundation start-up fund to FD a Canadian Institute of Health Research project grant to JM. DM is supported by Dr. David H. Hubel Postdoctoral Fellowship funded by the Dalhousie Medical Research Foundation. Publisher Copyright: Copyright {\textcopyright} 2022 Meghnem, Leong, Pinelli, Marshall and Di Cara.",

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doi = "10.3389/fcell.2022.856243",

language = "English",

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AU - Meghnem, Dihia

AU - Leong, Edwin

AU - Pinelli, Marinella

AU - Marshall, Jean S.

AU - Di Cara, Francesca

N1 - Funding Information: The Pex2 Mutant Mouse Strain used was 129S6.129-Pex2 /Mmmh(Null allele) () and was obtained from the Mutant Mouse Resource and Research Centre (MMRRC) supported by the NIH. The mice used for this experiment were Pex2 , Pex2 , Pex2 . Homozygous null mutant strains showed no Pex2 transcript and protein. Homozygous mutants in this congenic strain show variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygotes survive to birth but are hypotonic, do not feed and die on the day of birth. Homozygous mutants that survive in the postnatal period are obtained by mating congenic 129S6.129-Pex2 +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 +/- hybrids (designated Sw129) are then intercrossed to obtain Sw129-Pxmp3 −/− (indicated in the text as Pex2 ) mice. tm1Plf +/+ −/− +/− tm1Plf tm1Plf tm1Plf −/− Funding Information: This work was funded by a Discovery Grant from Natural Sciences and Engineering Research Council of Canada (NSERC) to FD, a Canada Foundation for Innovation (CFI) JELF equipment grant to FD, a Dalhousie Medical Research Foundation start-up fund to FD a Canadian Institute of Health Research project grant to JM. DM is supported by Dr. David H. Hubel Postdoctoral Fellowship funded by the Dalhousie Medical Research Foundation. Publisher Copyright: Copyright © 2022 Meghnem, Leong, Pinelli, Marshall and Di Cara.

PY - 2022/5/13

Y1 - 2022/5/13

N2 - 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.

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

Abstract

Bibliographical note

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PubMed: MeSH publication types

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