Metabolic Stress Boosts Humoral Responses In Vivo Independently of Inflammasome and Inflammatory Reaction

Adjuvant formulations boost humoral responses by acting through several, yet incompletely elucidated pathways. In this study, we show that oligomycin or 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) enhances Ab production when coinjected with T cell-dependent Ags. Oligomycin and AICAR lead to intracellular ATP reduction, suggesting that metabolic stress could be sensed by immune cells and leads to increased humoral responses. AICAR promotes IL-4 and IL-21 by naive Th cells but does not affect dendritic cell activation/maturation in vitro or in vivo. Accordingly, the adjuvant effect of AICAR or oligomycin does not require MyD88 or caspase-1 expression in vivo. Because AICAR is well tolerated in humans, this compound could represent a novel and safe adjuvant promoting humoral responses in vivo with a minimal reactogenicity.

[1]  B. Viollet,et al.  Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. , 2010, The Journal of clinical investigation.

[2]  T. Holowka,et al.  Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. , 2010, Blood.

[3]  C. Bernstein,et al.  Novel Anti-Inflammatory Action of 5-Aminoimidazole-4-carboxamide Ribonucleoside with Protective Effect in Dextran Sulfate Sodium-Induced Acute and Chronic Colitis , 2010, Journal of Pharmacology and Experimental Therapeutics.

[4]  M. Bachmann,et al.  Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner , 2010, The Journal of Immunology.

[5]  A. Bracht,et al.  Effects of metformin on glucose metabolism of perfused rat livers , 2010, Molecular and Cellular Biochemistry.

[6]  U. Reichl,et al.  Metabolic effects of influenza virus infection in cultured animal cells: Intra- and extracellular metabolite profiling , 2010, BMC Systems Biology.

[7]  M. Linterman,et al.  Signals that influence T follicular helper cell differentiation and function , 2010, Seminars in Immunopathology.

[8]  Philippa Marrack,et al.  Alum Induces Innate Immune Responses through Macrophage and Mast Cell Sensors, But These Sensors Are Not Required for Alum to Act As an Adjuvant for Specific Immunity1 , 2009, The Journal of Immunology.

[9]  Russell G. Jones,et al.  Enhancing CD8 T-cell memory by modulating fatty acid metabolism , 2009, Nature.

[10]  P. Marrack,et al.  Towards an understanding of the adjuvant action of aluminium , 2009, Nature Reviews Immunology.

[11]  W. Leonard,et al.  Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. , 2009, Blood.

[12]  J. Tschopp,et al.  Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome , 2009, Proceedings of the National Academy of Sciences.

[13]  B. Viollet,et al.  Beyond AICA riboside: In search of new specific AMP‐activated protein kinase activators , 2009, IUBMB life.

[14]  H. Hammad,et al.  Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome , 2008, The Journal of Immunology.

[15]  D. Hwang,et al.  Generation of T Follicular Helper Cells Is Mediated by Interleukin-21 but Independent of T Helper 1, 2, or 17 Cell Lineages (DOI: 10.1016/j.immuni.2008.05.009) , 2008 .

[16]  B. Cillero-Pastor,et al.  Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes. , 2008, Arthritis and rheumatism.

[17]  G. Núñez,et al.  The Nlrp3 inflammasome is critical for aluminium hydroxide‐mediated IL‐1β secretion but dispensable for adjuvant activity , 2008, European journal of immunology.

[18]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[19]  C. Mackay,et al.  A fundamental role for interleukin-21 in the generation of T follicular helper cells. , 2008, Immunity.

[20]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[21]  F. Re,et al.  Cutting Edge: Inflammasome Activation by Alum and Alum’s Adjuvant Effect Are Mediated by NLRP31 , 2008, The Journal of Immunology.

[22]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[23]  B. Viollet,et al.  AMP‐activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function , 2008, European journal of immunology.

[24]  M. Moser,et al.  Injection of lipopolysaccharide induces the migration of splenic neutrophils to the T cell area of the white pulp: role of CD14 and CXC chemokines , 2008, Journal of leukocyte biology.

[25]  G. Hui,et al.  Interleukin-6 has differential influence on the ability of adjuvant formulations to potentiate antibody responses to a Plasmodium falciparum blood-stage vaccine. , 2007, Vaccine.

[26]  F. Martinon,et al.  Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration , 2007, Cell Death and Differentiation.

[27]  M. Brown,et al.  Improving vaccines by incorporating immunological coadjuvants , 2007, Expert review of vaccines.

[28]  F. Sutterwala,et al.  The inflammasome in pathogen recognition and inflammation , 2007, Journal of leukocyte biology.

[29]  B. Guy,et al.  The perfect mix: recent progress in adjuvant research , 2007, Nature Reviews Microbiology.

[30]  B. Viollet,et al.  AMP-activated protein kinase-independent inhibition of hepatic mitochondrial oxidative phosphorylation by AICA riboside. , 2007, The Biochemical journal.

[31]  C. Daubenberger.  TLR9 agonists as adjuvants for prophylactic and therapeutic vaccines. , 2007, Current opinion in molecular therapeutics.

[32]  S. Mariathasan,et al.  Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation , 2007, Nature Reviews Immunology.

[33]  G. Kroemer,et al.  Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA , 2006, The Journal of cell biology.

[34]  D. Hardie,et al.  Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes , 2006, The Journal of experimental medicine.

[35]  F. Andris,et al.  CD4+CD25+ regulatory T cells control the magnitude ofT‐dependent humoral immune responses to exogenous antigens , 2006, European journal of immunology.

[36]  B. Viollet,et al.  5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. , 2006, Diabetes.

[37]  J. Bertin,et al.  Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. , 2006, Immunity.

[38]  P. Lipsky,et al.  IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells1 , 2005, The Journal of Immunology.

[39]  C. Mackay,et al.  Follicular B helper T cells in antibody responses and autoimmunity , 2005, Nature Reviews Immunology.

[40]  N. Glaichenhaus,et al.  TLR4 and Toll-IL-1 Receptor Domain-Containing Adapter-Inducing IFN-β, but Not MyD88, Regulate Escherichia coli-Induced Dendritic Cell Maturation and Apoptosis In Vivo1 , 2005, The Journal of Immunology.

[41]  Shailendra Giri,et al.  5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis1 , 2005, The Journal of Immunology.

[42]  D. Hardie.  The AMP-activated protein kinase pathway – new players upstream and downstream , 2004, Journal of Cell Science.

[43]  M. Moser,et al.  The heat stable antigen (CD24) is not required for the generation of CD4+ effector and memory T cells by dendritic cells in vivo. , 2004, Immunology letters.

[44]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[45]  F. Martinon,et al.  NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. , 2004, Immunity.

[46]  James E. Evans,et al.  Molecular identification of a danger signal that alerts the immune system to dying cells , 2003, Nature.

[47]  W. Beisel,et al.  Metabolic effects of infection on protein and energy status. , 2003, The Journal of nutrition.

[48]  A. Sher,et al.  A Critical Role for IL-21 in Regulating Immunoglobulin Production , 2002, Science.

[49]  Olle Ljunqvist,et al.  Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. , 2002, Diabetes.

[50]  C. Snapper,et al.  Endogenous Pro- and Anti-Inflammatory Cytokines Differentially Regulate an In Vivo Humoral Response to Streptococcus pneumoniae , 2002, Infection and Immunity.

[51]  R. Shaw,et al.  Rotavirus alters paracellular permeability and energy metabolism in Caco-2 cells. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[52]  M. Moser,et al.  The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells. , 2000, International immunology.

[53]  M. Rigoulet,et al.  Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I* , 2000, The Journal of Biological Chemistry.

[54]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[55]  P. De Baetselier,et al.  Regulation of Dendritic Cell Numbers and Maturation by Lipopolysaccharide in Vivo , 1996 .

[56]  P. Menasché,et al.  Acadesine: A new drug that may improve myocardial protection in coronary artery bypass grafting: Results of the first international multicenter study , 1995 .

[57]  M. Galiñanes,et al.  Protection against injury during ischemia and reperfusion by acadesine derivatives GP-1-468 and GP-1-668. Studies in the transplanted rat heart. , 1995, The Journal of thoracic and cardiovascular surgery.

[58]  M. Su,et al.  Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. , 1995, Science.

[59]  S. Aronson.  An initial multicenter, randomized controlled trial on the safety and efficacy of acadesine in patients undergoing coronary artery bypass graft surgery. , 1994, Anesthesia and analgesia.

[60]  J. Reves,et al.  An initial multicenter, randomized controlled trial on the safety and efficacy of acadesine in patients undergoing coronary artery bypass graft surgery. SPI Research Group. , 1994, Anesthesia and analgesia.

[61]  W. Nyhan,et al.  Treatment of Lesch-Nyhan syndrome with AICAR. , 1994, Advances in experimental medicine and biology.

[62]  H. Gruber,et al.  AICA‐Riboside: Safety, Tolerance, and Pharmacokinetics of a Novel Adenosine‐Regulating Agent , 1991, Journal of clinical pharmacology.