PMID- 34454372
OWN - NLM
STAT- MEDLINE
DCOM- 20211021
LR  - 20221003
IS  - 1878-5905 (Electronic)
IS  - 0142-9612 (Print)
IS  - 0142-9612 (Linking)
VI  - 277
DP  - 2021 Oct
TI  - Inhibition of glycolysis in the presence of antigen generates suppressive 
      antigen-specific responses and restrains rheumatoid arthritis in mice.
PG  - 121079
LID - S0142-9612(21)00435-X [pii]
LID - 10.1016/j.biomaterials.2021.121079 [doi]
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 (CD86(Lo)MHCII(+)) 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.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Mangal, Joslyn L
AU  - Mangal JL
AD  - Biological Design, Arizona State University, Tempe, AZ, 85281, USA.
FAU - Inamdar, Sahil
AU  - Inamdar S
AD  - Chemical Engineering, School for the Engineering of Matter, Transport, and 
      Energy, Arizona State University, Tempe, AZ, 85281, USA.
FAU - Le, Tien
AU  - Le T
AD  - Chemical Engineering, School for the Engineering of Matter, Transport, and 
      Energy, Arizona State University, Tempe, AZ, 85281, USA.
FAU - Shi, Xiaojian
AU  - Shi X
AD  - College of Health Solutions, Arizona State University, Phoenix, AZ, 85281, USA.
FAU - Curtis, Marion
AU  - Curtis M
AD  - Mayo Clinic, Department of Immunology, Scottsdale, AZ, 85259, USA.
FAU - Gu, Haiwei
AU  - Gu H
AD  - College of Health Solutions, Arizona State University, Phoenix, AZ, 85281, USA.
FAU - Acharya, Abhinav P
AU  - Acharya AP
AD  - Biological Design, Arizona State University, Tempe, AZ, 85281, USA; Chemical 
      Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona 
      State University, Tempe, AZ, 85281, USA; Materials Science and Engineering, 
      School for the Engineering of Matter, Transport, and Energy, Arizona State 
      University, Tempe, AZ, 85281, USA; Center for Immunotherapy, Vaccines and 
      Virotherapy, Arizona State University, Tempe, AZ, 85281, USA; Biomedical 
      Engineering, School of Biological and Health System Engineering, Arizona State 
      University, Tempe, AZ, 85281, USA. Electronic address: abhi.acharya@asu.edu.
LA  - eng
GR  - R01 AI155907/AI/NIAID NIH HHS/United States
GR  - R01 AR078343/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210820
PL  - Netherlands
TA  - Biomaterials
JT  - Biomaterials
JID - 8100316
RN  - 0 (PFK15)
RN  - 0 (Pyridines)
RN  - 0 (Quinolines)
SB  - IM
MH  - Animals
MH  - *Arthritis, Experimental
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - Dendritic Cells
MH  - Glycolysis
MH  - Mice
MH  - Mice, Inbred DBA
MH  - Pyridines
MH  - Quinolines
PMC - PMC8478855
MID - NIHMS1735958
OTO - NOTNLM
OT  - Autoimmune diseases
OT  - Biomaterials
OT  - Drug delivery
OT  - Immunoengineering
OT  - Immunometabolism
COIS- Competing interests: Abhinav P. Acharya is affiliated with a start-up company, 
      Immunometabolix, LLC. There are no other conflicts to declare. Declaration of 
      interests The authors declare the following financial interests/personal 
      relationships which may be considered as potential competing interests: Abhinav 
      P. Acharya reports financial support was provided by National Institutes of 
      Health. Abhinav P. Acharya has patent pending with Immunometabolix, LLC. N/A
EDAT- 2021/08/29 06:00
MHDA- 2022/10/04 06:00
PMCR- 2022/10/01
CRDT- 2021/08/28 20:25
PHST- 2021/05/30 00:00 [received]
PHST- 2021/08/13 00:00 [revised]
PHST- 2021/08/18 00:00 [accepted]
PHST- 2021/08/29 06:00 [pubmed]
PHST- 2022/10/04 06:00 [medline]
PHST- 2021/08/28 20:25 [entrez]
PHST- 2022/10/01 00:00 [pmc-release]
AID - S0142-9612(21)00435-X [pii]
AID - 10.1016/j.biomaterials.2021.121079 [doi]
PST - ppublish
SO  - Biomaterials. 2021 Oct;277:121079. doi: 10.1016/j.biomaterials.2021.121079. Epub 
      2021 Aug 20.