Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases

Systemic autoimmune diseases are characteristically associated with aberrant autoreactive innate and adaptive immune responses that lead to tissue damage and increased morbidity and mortality. Autoimmunity has been linked to alterations in the metabolic functions of immune cells (immunometabolism) and, more specifically, to mitochondrial dysfunction. Much has been written about immunometabolism in autoimmunity in general, so this Essay focuses on recent research into the role of mitochondrial dysfunction in the dysregulation of innate and adaptive immunity that is characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Enhancing the understanding of mitochondrial dysregulation in autoimmunity will hopefully contribute to accelerating the development of immunomodulatory treatments for these challenging diseases.

[1]  Alexandra F. Santos,et al.  Oral Tolerance Induction—Opportunities and Mechanisms , 2022, Foods.

[2]  D. Kofler,et al.  Regulatory T cells in rheumatoid arthritis: functions, development, regulation, and therapeutic potential , 2022, Cellular and Molecular Life Sciences.

[3]  L. Morel,et al.  Immunometabolic alterations in lupus: where do they come from and where do we go from there? , 2022, Current opinion in immunology.

[4]  Shiqiu Xiong,et al.  Oxidative phosphorylation regulates interleukin‐10 production in regulatory B cells via the extracellular signal‐related kinase pathway , 2022, Immunology.

[5]  A. Laurence,et al.  Transcription factor EB coordinates environmental cues to regulate T regulatory cells’ mitochondrial fitness and function , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Konig,et al.  Microbial pathways to subvert host immunity generate citrullinated neoantigens targeted in rheumatoid arthritis. , 2022, Current opinion in structural biology.

[7]  L. Blanco,et al.  Modulation of the Itaconate Pathway Attenuates Murine Lupus , 2022, Arthritis & rheumatology.

[8]  F. Huaux,et al.  Think Beyond Particle Cytotoxicity: When Self-Cellular Components Released After Immunogenic Cell Death Explain Chronic Disease Development , 2022, Frontiers in Toxicology.

[9]  A. Sawalha,et al.  The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope , 2022, Communications Biology.

[10]  Zhuotong Zeng,et al.  Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target , 2022, Frontiers in Immunology.

[11]  Y. Kochi,et al.  Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus , 2022, Annals of the Rheumatic Diseases.

[12]  F. Boisvert,et al.  Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus , 2022, Arthritis & rheumatology.

[13]  L. O’Neill,et al.  The role of itaconate in host defense and inflammation , 2022, The Journal of clinical investigation.

[14]  Mark S. Schmidt,et al.  Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes , 2022, The Journal of clinical investigation.

[15]  P. Kubes,et al.  Mitochondria in human neutrophils mediate killing of Staphylococcus aureus , 2021, Redox biology.

[16]  D. Sabatini,et al.  Fumarate is a terminal electron acceptor in the mammalian electron transport chain , 2021, Science.

[17]  C. Weyand,et al.  Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation , 2021, Nature Immunology.

[18]  L. O’Neill,et al.  The role of the electron transport chain in immunity , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  G. Hatch,et al.  Tafazzin deficiency impairs mitochondrial metabolism and function of lipopolysaccharide activated B lymphocytes in mice , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  S. Nourshargh,et al.  Endothelial cell autophagy keeps neutrophil trafficking under control , 2021, Autophagy.

[21]  S. Walmsley,et al.  Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle , 2021, Blood.

[22]  Christopher S. Wilson,et al.  Metabolic preconditioning in CD4+ T cells restores inducible immune tolerance in lupus-prone mice , 2021, JCI insight.

[23]  Hao Li,et al.  Glutathione peroxidase 4 regulated neutrophil ferroptosis induces systemic autoimmunity , 2021, Nature Immunology.

[24]  V. Pascual,et al.  Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE , 2021, Cell.

[25]  L. Morel,et al.  Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism , 2021, JCI insight.

[26]  M. Hafner,et al.  RNA Externalized by Neutrophil Extracellular Traps Promotes Inflammatory Pathways in Endothelial Cells , 2021, Arthritis & rheumatology.

[27]  B. Pulendran,et al.  Emerging concepts in the science of vaccine adjuvants , 2021, Nature reviews. Drug discovery.

[28]  B. Duvvuri,et al.  Mitochondrial N-formyl methionine peptides associate with disease activity as well as contribute to neutrophil activation in patients with rheumatoid arthritis. , 2021, Journal of autoimmunity.

[29]  T. Gaber,et al.  Hypoxia/HIF Modulates Immune Responses , 2021, Biomedicines.

[30]  B. Kaufman,et al.  IRGM1, a guardian of mitochondrial DAMP–mediated autoinflammation , 2021, Nature Immunology.

[31]  Wan-chi Lin,et al.  IRGM1 links mitochondrial quality control to autoimmunity , 2020, Nature Immunology.

[32]  OUP accepted manuscript , 2021, Rheumatology.

[33]  L. Tian,et al.  Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells. , 2020, Cell metabolism.

[34]  Shuang Chen,et al.  Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model , 2020, Frontiers in Immunology.

[35]  A. Hadjipanayis,et al.  Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4+ T Cell Effector Functions and Activation-Induced Metabolic Reprogramming , 2020, The Journal of Immunology.

[36]  M. V. Vander Heiden,et al.  Increased demand for NAD+ relative to ATP drives aerobic glycolysis , 2020, bioRxiv.

[37]  B. Faubert,et al.  Metabolic reprogramming and cancer progression , 2020, Science.

[38]  J. Craft,et al.  Kidney tissue hypoxia dictates T cell–mediated injury in murine lupus nephritis , 2020, Science Translational Medicine.

[39]  N. Huang,et al.  Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice , 2020, Lupus Science & Medicine.

[40]  J. Locasale,et al.  Metabolic regulation of epigenetic remodeling in immune cells. , 2020, Current opinion in biotechnology.

[41]  V. Shoshan-Barmatz,et al.  VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease , 2019, Science.

[42]  B. Lambrecht,et al.  Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis , 2019, bioRxiv.

[43]  S. Tait,et al.  Mitochondria as multifaceted regulators of cell death , 2019, Nature Reviews Molecular Cell Biology.

[44]  S. Rahman,et al.  Low-density granulocytes activate T cells and demonstrate a non-suppressive role in systemic lupus erythematosus , 2019, Annals of the rheumatic diseases.

[45]  V. Hoffmann,et al.  Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone , 2020, Arthritis & rheumatology.

[46]  A. Makrigiannakis,et al.  IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion , 2018, Cell reports.

[47]  R. Montgomery,et al.  HLA in transplantation , 2018, Nature Reviews Nephrology.

[48]  S. Seong,et al.  Cardiolipin activates antigen‐presenting cells via TLR2‐PI3K‐PKN1‐AKT/p38‐NF‐kB signaling to prime antigen‐specific naïve T cells in mice , 2018, European journal of immunology.

[49]  G. Anderson,et al.  T‐cell egress from the thymus: Should I stay or should I go? , 2018, Journal of leukocyte biology.

[50]  V. Papayannopoulos.  Neutrophil extracellular traps in immunity and disease , 2017, Nature Reviews Immunology.

[51]  G. Firestein,et al.  Immunopathogenesis of Rheumatoid Arthritis. , 2017, Immunity.

[52]  L. Criswell,et al.  Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses , 2016, Lupus Science & Medicine.

[53]  A. Perl,et al.  Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus , 2016, Science Signaling.

[54]  K. Elkon,et al.  Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease , 2015, Nature Medicine.

[55]  M. Kaplan,et al.  The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? , 2014, Current opinion in rheumatology.

[56]  J. Grigull,et al.  Experimental evidence that mutated-self peptides derived from mitochondrial DNA somatic mutations have the potential to trigger autoimmunity. , 2014, Human immunology.

[57]  T. Caza,et al.  Metabolic regulation of organelle homeostasis in lupus T cells. , 2012, Clinical immunology.

[58]  Matthias Kretzler,et al.  Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus , 2011, The Journal of Immunology.

[59]  W. Mccune,et al.  A Distinct Subset of Proinflammatory Neutrophils Isolated from Patients with Systemic Lupus Erythematosus Induces Vascular Damage and Synthesizes Type I IFNs , 2010, The Journal of Immunology.

[60]  Florey,et al.  The endothelial cell. , 1966, British medical journal.

[61]  M. Folan.  Immunological Tolerance , 1956, Journal of the Irish Medical Association.