Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

[1]  A. Mildner,et al.  Identification of environmental factors that promote intestinal inflammation , 2022, Nature.

[2]  A. Regev,et al.  Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity , 2021, Cell.

[3]  W. S. Denney,et al.  Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study , 2021, Nature Metabolism.

[4]  R. Caspi,et al.  Faculty Opinions recommendation of Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. , 2021, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[5]  Benjamin M. Scott,et al.  Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease , 2021, Nature Medicine.

[6]  R. Geiger,et al.  Metabolic modulation of tumours with engineered bacteria for immunotherapy , 2021, Nature.

[7]  Ryan L. Collins,et al.  Genome-wide enhancer maps link risk variants to disease genes , 2021, Nature.

[8]  C. Reis e Sousa,et al.  Dendritic Cells Revisited. , 2021, Annual review of immunology.

[9]  Jasmin Herz,et al.  Functional characterization of the dural sinuses as a neuroimmune interface , 2021, Cell.

[10]  N. Voelcker,et al.  Inducing immune tolerance with dendritic cell-targeting nanomedicines , 2020, Nature Nanotechnology.

[11]  V. Stanton,et al.  Tolerogenic nanoparticles suppress central nervous system inflammation , 2020, Proceedings of the National Academy of Sciences.

[12]  F. Ginhoux,et al.  Genetic models of human and mouse dendritic cell development and function , 2020, Nature reviews. Immunology.

[13]  L. Glimcher,et al.  XBP-1 and the unfolded protein response (UPR) , 2020, Nature Immunology.

[14]  Gregory F. Wu,et al.  cDC1 prime and are licensed by CD4 T cells to induce anti-tumour immunity , 2020, Nature.

[15]  Jianqin Gao,et al.  Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity , 2020, Nature Communications.

[16]  I. Amit,et al.  Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation , 2020, Nature Immunology.

[17]  N. Ajami,et al.  Dendritic cell–derived hepcidin sequesters iron from the microbiota to promote mucosal healing , 2020, Science.

[18]  V. Ganapathy,et al.  The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment , 2020, Oncogene.

[19]  J. Ragoussis,et al.  MAFG-driven astrocytes promote CNS inflammation , 2020, Nature.

[20]  C. Taylor,et al.  Hypoxia and Innate Immunity: Keeping Up with the HIFsters. , 2020, Annual review of immunology.

[21]  M. Theumer,et al.  Deficiency of CD73 activity promotes protective cardiac immunity against Trypanosoma cruzi infection but permissive environment in visceral adipose tissue. , 2020, Biochimica et biophysica acta. Molecular basis of disease.

[22]  Nicole M. Chapman,et al.  Metabolic coordination of T cell quiescence and activation , 2019, Nature Reviews Immunology.

[23]  D. Fotiadis,et al.  Mechanistic basis of L-lactate transport in the SLC16 solute carrier family , 2019, Nature Communications.

[24]  E. Segal,et al.  The pros, cons, and many unknowns of probiotics , 2019, Nature Medicine.

[25]  P. Carmeliet,et al.  Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR , 2019, Cell.

[26]  G. Getz,et al.  Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39 , 2019, Nature Neuroscience.

[27]  F. Quintana,et al.  The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease , 2019, Nature Reviews Immunology.

[28]  B. Becher,et al.  Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation , 2019, Science Immunology.

[29]  W. S. Denney,et al.  An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans , 2019, Science Translational Medicine.

[30]  Quynh-Mai Pham,et al.  Optimal protection against Salmonella infection requires noncirculating memory , 2018, Proceedings of the National Academy of Sciences.

[31]  Joseph G Ibrahim,et al.  Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences , 2018, bioRxiv.

[32]  W. S. Denney,et al.  Translational Development of Microbiome‐Based Therapeutics: Kinetics of E. coli Nissle and Engineered Strains in Humans and Nonhuman Primates , 2017, Clinical and translational science.

[33]  L. O’Neill,et al.  Mitochondria are the powerhouses of immunity , 2017, Nature Immunology.

[34]  Rob Patro,et al.  Salmon provides fast and bias-aware quantification of transcript expression , 2017, Nature Methods.

[35]  Brice Enjalbert,et al.  Acetate fluxes in Escherichia coli are determined by the thermodynamic control of the Pta-AckA pathway , 2017, Scientific Reports.

[36]  Y. Li,et al.  Feedback Control of AHR Signaling Regulates Intestinal Immunity , 2017, Nature.

[37]  M. Tekin,et al.  Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity , 2016, Cell.

[38]  E. Cummins,et al.  The role of HIF in immunity and inflammation. , 2016, Molecular aspects of medicine.

[39]  Juan R. Cubillos-Ruiz,et al.  ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis , 2015, Cell.

[40]  C. Clish,et al.  Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α , 2015, Nature Medicine.

[41]  M. Daly,et al.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants , 2014, Nature.

[42]  A. Regev,et al.  Preparation of Single‐Cell RNA‐Seq Libraries for Next Generation Sequencing , 2014, Current protocols in molecular biology.

[43]  V. Kuchroo,et al.  IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39 , 2013, Nature Immunology.

[44]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[45]  Julie L. Engers,et al.  Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway. , 2012, Bioorganic & medicinal chemistry letters.

[46]  G. Semenza,et al.  Hypoxia-Inducible Factors in Physiology and Medicine , 2012, Cell.

[47]  J. Enríquez,et al.  Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity. , 2011, Cell metabolism.

[48]  Xi Chen,et al.  TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages , 2010, Nature Immunology.

[49]  Manuel Cánovas,et al.  An insight into the role of phosphotransacetylase (pta) and the acetate/acetyl-CoA node in Escherichia coli , 2009, Microbial cell factories.

[50]  U. Sonnenborn,et al.  The non-pathogenic Escherichia coli strain Nissle 1917 – features of a versatile probiotic , 2009 .

[51]  Atsushi Miyawaki,et al.  Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice , 2008, Proceedings of the National Academy of Sciences.

[52]  I. Hassinen,et al.  Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates , 2007, Journal of Biological Chemistry.

[53]  R. DePinho,et al.  Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Yuen-Li Chung,et al.  HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. , 2005, Cancer cell.

[56]  M. Hofker.  Faculty Opinions recommendation of PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. , 2003 .

[57]  H. Weiner,et al.  Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis , 2003, The Journal of experimental medicine.

[58]  G. Trinchieri,et al.  Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. , 1998, Journal of immunology.

[59]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.