International immunopharmacology · 2026
Inhibition of SUMOylation by anacardic acid inhibits adaptive immunity and the development of EAE.
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Kim Kwang, Ljunggren-Rose Åsa, Yarlagadda Medha, Vergne Matthew J, Sriram Subramaniam
Аннотация
OBJECTIVE: Small ubiquitin-like modifiers (SUMO) are reversible post-translational modifiers of intracellular proteins. SUMOylation plays an important regulatory role in both innate and adaptive immunity. The natural compound anacardic acid (AA) has been shown to bind and inhibit the SUMO-activating enzyme E1, the first enzyme in the SUMOylation pathway. Here, we examined the consequences of AA treatment on the development of innate and adaptive immune responses in vitro and in vivo.
METHODS: We examined the inhibitory effects of anacardic acid on SUMOylation and de-SUMOylation both in vitro and in vivo. The in vitro studies on the effect of anacardic acid on the development of an immune response were conducted in RAW264.7 cells and naïve or antigen-driven splenocytes.
RESULTS: AA inhibited activation of NF-κB by preventing SUMOylation of NEMO, a key requirement for activation of the canonical NF-κB pathway. Stimulation of splenocytes with LPS, a known immunostimulant, resulted in reduced production of inflammatory mediators, including IL-12, IL-23, TNF-α, and iNOS, in the presence of AA. In antigen-primed lymphocytes stimulated with MOGp₃₅-₅₅, AA reduced the induction of IL-17, IFN-γ, TNF-α, IL-6, and GM-CSF. Following transfer of MOGp₃₅-₅₅-primed lymphocytes into naïve mice, AA treatment significantly reduced clinical paralysis and pathological CNS inflammation in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis.
CONCLUSION: The ability of AA to inhibit NF-κB-driven inflammatory response and CNS inflammation after autoreactive T cells are already primed and circulating suggests that AA may have therapeutic potential in established Th1/Th17-mediated inflammatory diseases.
METHODS: We examined the inhibitory effects of anacardic acid on SUMOylation and de-SUMOylation both in vitro and in vivo. The in vitro studies on the effect of anacardic acid on the development of an immune response were conducted in RAW264.7 cells and naïve or antigen-driven splenocytes.
RESULTS: AA inhibited activation of NF-κB by preventing SUMOylation of NEMO, a key requirement for activation of the canonical NF-κB pathway. Stimulation of splenocytes with LPS, a known immunostimulant, resulted in reduced production of inflammatory mediators, including IL-12, IL-23, TNF-α, and iNOS, in the presence of AA. In antigen-primed lymphocytes stimulated with MOGp₃₅-₅₅, AA reduced the induction of IL-17, IFN-γ, TNF-α, IL-6, and GM-CSF. Following transfer of MOGp₃₅-₅₅-primed lymphocytes into naïve mice, AA treatment significantly reduced clinical paralysis and pathological CNS inflammation in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis.
CONCLUSION: The ability of AA to inhibit NF-κB-driven inflammatory response and CNS inflammation after autoreactive T cells are already primed and circulating suggests that AA may have therapeutic potential in established Th1/Th17-mediated inflammatory diseases.