TY - JOUR
T1 - Inhibition of glycolysis in the presence of antigen generates suppressive antigen-specific responses and restrains rheumatoid arthritis in mice
AU - Mangal, Joslyn L.
AU - Inamdar, Sahil
AU - Le, Tien
AU - Shi, Xiaojian
AU - Curtis, Marion
AU - Gu, Haiwei
AU - Acharya, Abhinav P.
N1 - Funding Information:
The authors would like to acknowledge the Flow Cytometry Core, the Regenerative Medicine Imaging Facility, the KED Genomics Core, the FEI at Erying Materials Center, the Advanced Light Microscopy Facilities, and the Department of Animal Care and Technologies at Arizona State University. Additionally, the authors would like to thank Dr. Seo, School of Molecular Sciences, Arizona State University for providing access to dynamic light scatter. Funding: The authors would also like to acknowledge the startup funds provided by Arizona State University to Abhinav P. Acharya for the completion of this study, NIH 1R01AI155907-01 and NIH R01AR078343. Author contributions: Joslyn L. Mangal designed and preformed experiments, analyzed data, and wrote the manuscript. Sahil Inamdar, Tien Le and Xiaojian Shi performed experiments. Marion Curtis assisted with extracellular flux assays, Haiwei Gu assisted with metabolomics. Abhinav P. Acharya helped design experiments and wrote the manuscript. Competing interests: Abhinav P. Acharya is affiliated with a start-up company, Immunometabolix, LLC. There are no other conflicts to declare. Data and materials availability: All data needed to evaluate the conclusions are present in the manuscript and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. The raw data required to reproduce these findings are available upon request from the authors. The processed data required to reproduce these findings are available upon request from the authors.
Funding Information:
The authors would like to acknowledge the Flow Cytometry Core, the Regenerative Medicine Imaging Facility, the KED Genomics Core, the FEI at Erying Materials Center, the Advanced Light Microscopy Facilities, and the Department of Animal Care and Technologies at Arizona State University. Additionally, the authors would like to thank Dr. Seo, School of Molecular Sciences, Arizona State University for providing access to dynamic light scatter. Funding : The authors would also like to acknowledge the startup funds provided by Arizona State University to Abhinav P. Acharya for the completion of this study, NIH 1R01AI155907-01 and NIH R01AR078343 . Author contributions: Joslyn L. Mangal designed and preformed experiments, analyzed data, and wrote the manuscript. Sahil Inamdar, Tien Le and Xiaojian Shi performed experiments. Marion Curtis assisted with extracellular flux assays, Haiwei Gu assisted with metabolomics. Abhinav P. Acharya helped design experiments and wrote the manuscript. Competing interests: Abhinav P. Acharya is affiliated with a start-up company, Immunometabolix, LLC. There are no other conflicts to declare. Data and materials availability: All data needed to evaluate the conclusions are present in the manuscript and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. The raw data required to reproduce these findings are available upon request from the authors. The processed data required to reproduce these findings are available upon request from the authors.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/10
Y1 - 2021/10
N2 - Dendritic cells (DCs) rely on glycolysis for their energy needs to induce pro-inflammatory antigen-specific immune responses. Therefore, inhibiting DC glycolysis, while presenting the self-antigen, may prevent pro-inflammatory antigen-specific immune responses. Previously we demonstrated that microparticles with alpha-ketoglutarate (aKG) in the polymer backbone (paKG MPs) were able to generate anti-inflammatory DCs by sustained delivery of the aKG metabolite, and by modulating energy metabolism of DCs. Herein, we demonstrate that paKG MPs-based delivery of a glycolytic inhibitor, PFK15, using paKG MPs induces anti-inflammatory DCs (CD86LoMHCII+) by down-regulating glycolysis, CD86, tnf and IL-6 genes, while upregulating oxidative phosphorylation (OXPHOS) and mitochondrial genes. Furthermore, paKG MPs delivering PFK15 and a self-antigen, collagen type II (bc2), in vivo, in a collagen-induced autoimmune arthritis (CIA) mouse model, normalized paw inflammation and arthritis score, by generating antigen-specific immune responses. Specifically, these formulations were able to reduce activation of DCs in draining lymph nodes and impressively generated proliferating bc2-specific anti-inflammatory regulatory T cells in joint-associated popliteal lymph nodes. These data strongly suggest that sustained glycolytic inhibition of DCs in the presence of an antigen can induce antigen-specific immunosuppressive responses, therefore, generating a technology that can be applicable for treating autoimmune diseases.
AB - Dendritic cells (DCs) rely on glycolysis for their energy needs to induce pro-inflammatory antigen-specific immune responses. Therefore, inhibiting DC glycolysis, while presenting the self-antigen, may prevent pro-inflammatory antigen-specific immune responses. Previously we demonstrated that microparticles with alpha-ketoglutarate (aKG) in the polymer backbone (paKG MPs) were able to generate anti-inflammatory DCs by sustained delivery of the aKG metabolite, and by modulating energy metabolism of DCs. Herein, we demonstrate that paKG MPs-based delivery of a glycolytic inhibitor, PFK15, using paKG MPs induces anti-inflammatory DCs (CD86LoMHCII+) by down-regulating glycolysis, CD86, tnf and IL-6 genes, while upregulating oxidative phosphorylation (OXPHOS) and mitochondrial genes. Furthermore, paKG MPs delivering PFK15 and a self-antigen, collagen type II (bc2), in vivo, in a collagen-induced autoimmune arthritis (CIA) mouse model, normalized paw inflammation and arthritis score, by generating antigen-specific immune responses. Specifically, these formulations were able to reduce activation of DCs in draining lymph nodes and impressively generated proliferating bc2-specific anti-inflammatory regulatory T cells in joint-associated popliteal lymph nodes. These data strongly suggest that sustained glycolytic inhibition of DCs in the presence of an antigen can induce antigen-specific immunosuppressive responses, therefore, generating a technology that can be applicable for treating autoimmune diseases.
KW - Autoimmune diseases
KW - Biomaterials
KW - Drug delivery
KW - Immunoengineering
KW - Immunometabolism
UR - http://www.scopus.com/inward/record.url?scp=85113443485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85113443485&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2021.121079
DO - 10.1016/j.biomaterials.2021.121079
M3 - Article
C2 - 34454372
AN - SCOPUS:85113443485
VL - 277
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
M1 - 121079
ER -