Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs. [Display omitted] •A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) activates NRF2•C151 of the chaperone protein KEAP1 is necessary for NRF2 activation by indomethacin•Indomethacin reduces inflammation in endotoxemia and gout models dependent on NRF2 The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is ubiquitous. Herein, Eisenstein et. al., identify a noncanonical mechanism of action for the anti-inflammatory activity of NSAIDs through activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). In endotoxemia and gout models, indomethacin improved inflammation in an NRF2-dependent manner.