posted on 2021-06-24, 15:04authored byChristopher
J. Genito, Meital Eckshtain-Levi, Zayda L. Piedra-Quintero, Sai Archana Krovi, Abriana Kroboth, Rebeca T. Stiepel, Mireia Guerau-de-Arellano, Eric M. Bachelder, Kristy M. Ainslie
Macrophage-mediated inflammation
drives autoimmune and chronic
inflammatory diseases. Treatment with anti-inflammatory agents can
be an effective strategy to reduce this inflammation; however, high
concentrations of these agents can have immune-dampening and other
serious side effects. Synergistic combination of anti-inflammatory
agents can mitigate dosing by requiring less drug. Multiple anti-inflammatory
agents were evaluated in combination for synergistic inhibition of
macrophage inflammation. The most potent synergy was observed between
dexamethasone (DXM) and fumaric acid esters (e.g., monomethyl fumarate
(MMF)). Furthermore, this combination was found to synergistically
inhibit inflammatory nuclear factor κB (NF-κB) transcription
factor activity. The optimal ratio for synergy was determined to be
1:1, and DXM and MMF were conjugated by esterification at this molar
ratio. The DXM–MMF conjugate displayed improved inhibition
of inflammation over the unconjugated combination in both murine and
human macrophages. In the treatment of human donor monocyte-derived
macrophages, the combination of DXM and MMF significantly inhibited
inflammatory gene expression downstream of NF-κB and overall
performed better than either agent alone. Further, the DXM–MMF
conjugate significantly inhibited expression of NOD-, LRR-, and pyrin
domain-containing protein 3 (NLRP3) inflammasome-associated genes.
The potent anti-inflammatory activity of the DXM–MMF conjugate
in human macrophages indicates that it may have benefits in the treatment
of autoimmune and inflammatory diseases.