The Mitochondria-Modulating Small Molecule TEM1657 Suppresses NFKBIZ Pathway and Resolves Th17-Driven Psoriatic Inflammation
GAUTAM, P.; SALWINSKI, A.; Abdelwahab, A. B.; JALCE, G.; BOULANGE, L.; BETTINGER, J.; BROUARD, J. J. S.; ETLICHER, A.; PEROUF, R.; HALPER, J.; MILLARD, M.; DE ISLA, N.; HANNEWALD, P.; GINGLINGER, J.-F.; RUBIO, M.-T.; JOUZEAU, J.-Y.; BOURGAUD, F.; MOULIN, D.
Show abstract
Psoriasis is a chronic skin disease characterized by red, scaly plaques mainly driven by dysregulated T cells that induce keratinocytes (KCs) proliferation and inflammation. Despite significant advancements in disease management through biologics and topical therapies, these treatments offer only temporary relief and fail to prevent disease recurrence. Considering the current therapeutic needs, we described herein a novel small molecule TEM1657, derived from 3,5-dicaffeoylquinic acid with anti-inflammatory potency in imiquimod-induced psoriasis mouse model as well as in Th17-stimulated KCs. Mechanistically, its action is mediated through modulation of mitochondrial dynamics, specifically via OPA1, an inner mitochondrial membrane protein that alters mitochondrial calcium influx, and further impacts cellular bioenergetics. Moreover, TEM1657 rapidly suppresses transcription of NFKBIZ and various other psoriasis-associated genes. These observations highlighted a pathway that represents an innovative target in psoriasis and other NFKBIZ-related disorders.
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