There is experimental and clinical evidence that some exanthematous allergic drug hypersensitivity reactions are mediated by drug-specific T cells. We hypothesized that the capacity of certain drugs to directly stimulate the innate immune system may contribute to generate drug-specific T cells. Here we analyzed whether abacavir, an HIV-1 reverse transcriptase inhibitor often inducing severe delayed-type drug hypersensitivity, can trigger innate immune activation that may contribute to its allergic potential. We show that abacavir fails to generate direct innate immune activation in human monocytes but potently triggers IL-1β release upon proinflammatory priming with phorbol ester or Toll-like receptor stimulation. IL-1β processing and secretion was sensitive to Caspase-1 inhibition, NLRP3 knock-down and K+ efflux inhibition and was not observed with other non-allergenic nucleoside reverse transcriptase inhibitors identifying abacavir as specific inflammasome activator. It further correlated with dose-dependent mitochondrial ROS production and cytotoxicity indicating that inflammasome activation resulted from mitochondrial damage. However, both NLRP3 depletion and inhibition of K+ efflux mitigated abacavir-induced mitochondrial ROS production and cytotoxicity suggesting that these processes were secondary to NLRP3 activation. Instead, depletion of Cardiolipin synthase 1 abolished ABC-induced IL-1β secretion, suggesting that mitochondrial Cardiolipin release may trigger ABC-induced inflammasome activation. Our data identify abacavir as novel inflammasome-stimulating drug allergen. They implicate a potential contribution of innate immune activation to medication-induced delayed-type hypersensitivity, which may stimulate new concepts for treatment and prevention of drug allergies.
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