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

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

doi:10.1016/j.celrep.2022.110433

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

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

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

16 Citas (Scopus)

Resumen

Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.

Idioma original	English
Número de artículo	110433
Publicación	Cell Reports
Volumen	38
N.º	9
DOI	https://doi.org/10.1016/j.celrep.2022.110433
Estado	Published - mar. 1 2022

Nota bibliográfica

Funding Information:
This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D. a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D. a Canada Foundation for Innovation JELF equipment grant to F.D. a Dalhousie Medical Research Foundation start-up fund to F.D. an IWK Foundation graduate student scholarship to Y.M. an IWK Foundation summer studentship to I.E. and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W. Flow cytometry was performed at the University of Alberta, Faculty of Medicine & Dentistry Flow Cytometry Facility and at the Dalhousie University, Faculty of Medicine Flow Cytometry Core Facility. Microscopy was performed at the Dalhousie University, Faculty of Medicine Cellular and Molecular Digital Imaging and Zebrafish Core Facility. We thank Stephen Withefield and Brianne Lindsay for help with microscopy, and Aja Rieger and Derek Rowter for training and for technical help in flow cytometry. David Malloy provided access to the Dalhousie Zebrafish Core Fluorescent Stereomicroscopes for Drosophila imaging. Lipidomic analysis was performed at the University of Amsterdam Medical Centers, Laboratory Genetic Metabolic Diseases, Core Facility Metabolomics. A.S.N. F.D. and B.D.P. performed experiments using Drosophila cell lines. S.M. performed IF microscopy of Rho1-transfected cells. J.L. and F.D. did the PIP2 analysis. Y.M. characterized the FOXO response to peroxisomal metabolic defects. C.M.W. I.E. and K.A.F. made lipid and Rho1 reporter constructs and performed microscopy of transfected cells. R.L.C. P.M.S. F.D. and B.D.P. performed mouse experiments. P.M.S. performed flow cytometry analysis. D.P.M. performed live-imaging analysis. A.P.M. and Y.H. advised on experiments using mice. L.H.B. and N.P. analyzed mitochondrial activities. B.D. supplied cells from KD and JIA patients. C.W. established the Pex2 mutant mouse colony. A.J.S. constructed RNA libraries for next generation sequencing analysis. R.A.R. advised on experimental design and contributed to writing the manuscript. F.D. conceived the project, performed experiments and analyses, and wrote the manuscript with B.D.P. and R.A.R. All authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

Funding Information:
This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D., a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D., a Canada Foundation for Innovation JELF equipment grant to F.D., a Dalhousie Medical Research Foundation start-up fund to F.D., an IWK Foundation graduate student scholarship to Y.M., an IWK Foundation summer studentship to I.E., and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W.

Funding Information:
The Pex2 mutant mouse strain used was 129S6.129-Pex2 tm1Plf /Mmmh (null allele) ( Faust and Hatten, 1997 ) and was obtained from the Mutant Mouse Resource & Research Centers (MMRRC) supported by the National Institutes of Health. The mice used for the experiments reported herein were Pex2 +/+ , Pex2 -/- and Pex2 +/- . Homozygous null mutants showed no Pex2 transcript and no Pex2 protein. Homozygous null mutants in the congenic strain 129S6.129-Pex2 tm1Plf +/- showed variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygous null mutants survived to birth but were hypotonic, did not feed, and died on the day of birth. Homozygous null mutant mice that survived into the postnatal period were obtained by mating congenic 129S6.129-Pex2 tm1Plf +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 tm1Plf +/- hybrids (designated Sw129) were then intercrossed to obtain Sw129-Pxmp3 tm1Plf -/- (indicated in the text as Pex2 -/- ) mice.

Publisher Copyright:
© 2022 The Author(s)

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.celrep.2022.110433

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Nath, A. S., Parsons, B. D., Makdissi, S., Chilvers, R. L., Mu, Y., Weaver, C. M., Euodia, I., Fitze, K. A., Long, J., Scur, M., Mackenzie, D. P., Makrigiannis, A. P., Pichaud, N., Boudreau, L. H., Simmonds, A. J., Webber, C. A., Derfalvi, B., Hammon, Y., Rachubinski, R. A., & Di Cara, F. (2022). Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses. Cell Reports, 38(9), Artículo 110433. https://doi.org/10.1016/j.celrep.2022.110433

Nath, AS, Parsons, BD, Makdissi, S, Chilvers, RL, Mu, Y, Weaver, CM, Euodia, I, Fitze, KA, Long, J, Scur, M, Mackenzie, DP, Makrigiannis, AP, Pichaud, N, Boudreau, LH, Simmonds, AJ, Webber, CA, Derfalvi, B, Hammon, Y, Rachubinski, RA & Di Cara, F 2022, 'Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses', Cell Reports, vol. 38, n.º 9, 110433. https://doi.org/10.1016/j.celrep.2022.110433

@article{fa67606ca8974cb394ee485fc723e5ae,

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

abstract = "Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.",

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

note = "Funding Information: This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D. a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D. a Canada Foundation for Innovation JELF equipment grant to F.D. a Dalhousie Medical Research Foundation start-up fund to F.D. an IWK Foundation graduate student scholarship to Y.M. an IWK Foundation summer studentship to I.E. and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W. Flow cytometry was performed at the University of Alberta, Faculty of Medicine & Dentistry Flow Cytometry Facility and at the Dalhousie University, Faculty of Medicine Flow Cytometry Core Facility. Microscopy was performed at the Dalhousie University, Faculty of Medicine Cellular and Molecular Digital Imaging and Zebrafish Core Facility. We thank Stephen Withefield and Brianne Lindsay for help with microscopy, and Aja Rieger and Derek Rowter for training and for technical help in flow cytometry. David Malloy provided access to the Dalhousie Zebrafish Core Fluorescent Stereomicroscopes for Drosophila imaging. Lipidomic analysis was performed at the University of Amsterdam Medical Centers, Laboratory Genetic Metabolic Diseases, Core Facility Metabolomics. A.S.N. F.D. and B.D.P. performed experiments using Drosophila cell lines. S.M. performed IF microscopy of Rho1-transfected cells. J.L. and F.D. did the PIP2 analysis. Y.M. characterized the FOXO response to peroxisomal metabolic defects. C.M.W. I.E. and K.A.F. made lipid and Rho1 reporter constructs and performed microscopy of transfected cells. R.L.C. P.M.S. F.D. and B.D.P. performed mouse experiments. P.M.S. performed flow cytometry analysis. D.P.M. performed live-imaging analysis. A.P.M. and Y.H. advised on experiments using mice. L.H.B. and N.P. analyzed mitochondrial activities. B.D. supplied cells from KD and JIA patients. C.W. established the Pex2 mutant mouse colony. A.J.S. constructed RNA libraries for next generation sequencing analysis. R.A.R. advised on experimental design and contributed to writing the manuscript. F.D. conceived the project, performed experiments and analyses, and wrote the manuscript with B.D.P. and R.A.R. All authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Funding Information: This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D., a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D., a Canada Foundation for Innovation JELF equipment grant to F.D., a Dalhousie Medical Research Foundation start-up fund to F.D., an IWK Foundation graduate student scholarship to Y.M., an IWK Foundation summer studentship to I.E., and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W. Funding Information: The Pex2 mutant mouse strain used was 129S6.129-Pex2 tm1Plf /Mmmh (null allele) ( Faust and Hatten, 1997 ) and was obtained from the Mutant Mouse Resource & Research Centers (MMRRC) supported by the National Institutes of Health. The mice used for the experiments reported herein were Pex2 +/+ , Pex2 -/- and Pex2 +/- . Homozygous null mutants showed no Pex2 transcript and no Pex2 protein. Homozygous null mutants in the congenic strain 129S6.129-Pex2 tm1Plf +/- showed variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygous null mutants survived to birth but were hypotonic, did not feed, and died on the day of birth. Homozygous null mutant mice that survived into the postnatal period were obtained by mating congenic 129S6.129-Pex2 tm1Plf +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 tm1Plf +/- hybrids (designated Sw129) were then intercrossed to obtain Sw129-Pxmp3 tm1Plf -/- (indicated in the text as Pex2 -/- ) mice. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = mar,

day = "1",

doi = "10.1016/j.celrep.2022.110433",

language = "English",

volume = "38",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "9",

}

TY - JOUR

T1 - Modulation of the cell membrane lipid milieu by peroxisomal β-oxidation induces Rho1 signaling to trigger inflammatory responses

AU - Nath, Anu S.

AU - Parsons, Brendon D.

AU - Makdissi, Stephanie

AU - Chilvers, Rebecca L.

AU - Mu, Yizhu

AU - Weaver, Ceileigh M.

AU - Euodia, Irene

AU - Fitze, Katherine A.

AU - Long, Juyang

AU - Scur, Michal

AU - Mackenzie, Duncan P.

AU - Makrigiannis, Andrew P.

AU - Pichaud, Nicolas

AU - Boudreau, Luc H.

AU - Simmonds, Andrew J.

AU - Webber, Christine A.

AU - Derfalvi, Beata

AU - Hammon, Yannick

AU - Rachubinski, Richard A.

AU - Di Cara, Francesca

N1 - Funding Information: This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D. a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D. a Canada Foundation for Innovation JELF equipment grant to F.D. a Dalhousie Medical Research Foundation start-up fund to F.D. an IWK Foundation graduate student scholarship to Y.M. an IWK Foundation summer studentship to I.E. and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W. Flow cytometry was performed at the University of Alberta, Faculty of Medicine & Dentistry Flow Cytometry Facility and at the Dalhousie University, Faculty of Medicine Flow Cytometry Core Facility. Microscopy was performed at the Dalhousie University, Faculty of Medicine Cellular and Molecular Digital Imaging and Zebrafish Core Facility. We thank Stephen Withefield and Brianne Lindsay for help with microscopy, and Aja Rieger and Derek Rowter for training and for technical help in flow cytometry. David Malloy provided access to the Dalhousie Zebrafish Core Fluorescent Stereomicroscopes for Drosophila imaging. Lipidomic analysis was performed at the University of Amsterdam Medical Centers, Laboratory Genetic Metabolic Diseases, Core Facility Metabolomics. A.S.N. F.D. and B.D.P. performed experiments using Drosophila cell lines. S.M. performed IF microscopy of Rho1-transfected cells. J.L. and F.D. did the PIP2 analysis. Y.M. characterized the FOXO response to peroxisomal metabolic defects. C.M.W. I.E. and K.A.F. made lipid and Rho1 reporter constructs and performed microscopy of transfected cells. R.L.C. P.M.S. F.D. and B.D.P. performed mouse experiments. P.M.S. performed flow cytometry analysis. D.P.M. performed live-imaging analysis. A.P.M. and Y.H. advised on experiments using mice. L.H.B. and N.P. analyzed mitochondrial activities. B.D. supplied cells from KD and JIA patients. C.W. established the Pex2 mutant mouse colony. A.J.S. constructed RNA libraries for next generation sequencing analysis. R.A.R. advised on experimental design and contributed to writing the manuscript. F.D. conceived the project, performed experiments and analyses, and wrote the manuscript with B.D.P. and R.A.R. All authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Funding Information: This work was funded by a Project Grant from the Canadian Institutes of Health Research to F.D., a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada to F.D., a Canada Foundation for Innovation JELF equipment grant to F.D., a Dalhousie Medical Research Foundation start-up fund to F.D., an IWK Foundation graduate student scholarship to Y.M., an IWK Foundation summer studentship to I.E., and a GIVETOLIVE sponsored Beatrice Hunter summer studentship to C.M.W. Funding Information: The Pex2 mutant mouse strain used was 129S6.129-Pex2 tm1Plf /Mmmh (null allele) ( Faust and Hatten, 1997 ) and was obtained from the Mutant Mouse Resource & Research Centers (MMRRC) supported by the National Institutes of Health. The mice used for the experiments reported herein were Pex2 +/+ , Pex2 -/- and Pex2 +/- . Homozygous null mutants showed no Pex2 transcript and no Pex2 protein. Homozygous null mutants in the congenic strain 129S6.129-Pex2 tm1Plf +/- showed variable embryonic lethality, starting at ∼E11. Approximately 20% of homozygous null mutants survived to birth but were hypotonic, did not feed, and died on the day of birth. Homozygous null mutant mice that survived into the postnatal period were obtained by mating congenic 129S6.129-Pex2 tm1Plf +/- mice with wild-type Swiss Webster strain mice. F1-Pxmp3 tm1Plf +/- hybrids (designated Sw129) were then intercrossed to obtain Sw129-Pxmp3 tm1Plf -/- (indicated in the text as Pex2 -/- ) mice. Publisher Copyright: © 2022 The Author(s)

PY - 2022/3/1

Y1 - 2022/3/1

N2 - Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.

AB - Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.

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

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