NRF2 activator A-1396076 ameliorates inflammation in autoimmune disease models by inhibiting antigen dependent T cell activation
| Autor: | Paul M. Jung, Craig Wallace, Sonia Terrillon, Rachel Twomey, Paul L. Richardson, Peter Bousquet, Min Hu, Michelle Hart, Carolyn A. Cuff, Christian Goess, Tim Esbenshade, Martha Mayo, Marian Namovic, Diana Donnelly-Roberts, Suzanne Mathieu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Research paper
biology Chemistry Activator (genetics) Triterpenoid T cell Immunology Antigen presentation Inflammation respiratory system RC581-607 medicine.anatomical_structure Antigen Oxidative stress medicine Cancer research biology.protein Immunology and Allergy medicine.symptom Antibody Antioxidant Immunologic diseases. Allergy Transcription factor Ex vivo |
| Zdroj: | Journal of Translational Autoimmunity, Vol 4, Iss, Pp 100079-(2021) Journal of Translational Autoimmunity |
| ISSN: | 2589-9090 |
| Popis: | Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We have identified A-1396076, a potent and selective NRF2 activator with demonstrated KEAP1 binding and modulation of cellular NRF2 mediated effects. In vivo administration of A-1396076 inhibits inflammation across several rodent models of autoimmunity when administered at or before the time of antigen challenge while also inducing NRF2 modulated gene transcription in the liver of the animals. It was not effective when administered after the time of antigen challenge or in a T cell independent model of arthritis induced by passive transfer of anti-collagen antibodies. A-1396076 inhibited antigen dependent T cell activation as measured by IFN-γ production in an ex vivo re-stimulation assay and following anti-CD3 challenge of MOG-sensitized mice. A-1396076 reduced costimulatory molecule expression on dendritic cells in the lungs of OVA LPS challenged mice suggesting that the mechanism of T cell inhibition was mediated at least partially by interfering with antigen presentation. These data suggest that NRF2 activation may be an effective strategy to dampen inflammation for treatment of autoimmune disease. Highlights • A-1396076 is a potent and selective NRF2 activator. • A-1396076 induces NRF2 dependent gene program in vivo. • A-1396076 inhibits multiple inflammatory models with prophylactic dosing. • A-1396076 inhibits antigen dependent T cell activation. • A-1396076 reduces costimulatory molecules on dendritic cells in vivo. |
| Databáze: | OpenAIRE |
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