A carbamazepine metabolite activates NLRP3 and controls skin homing of CD8+ T-cells in SJS/TEN.

Abstract

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with extensive keratinocyte death. Carbamazepine (CBZ), the most commonly implicated drug in SJS/TEN, is metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) into carbamazepine-10,11-epoxide (CBZE) in the liver. While CD8⁺ cytotoxic T cells play an important role in SJS/TEN, the underlying mechanism of exuberant immune response by CD8⁺ T cells in these conditions remains incompletely understood.

Objectives: To examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN.

Methods: The expression of the NLRP3 inflammasome complex in skin lesions, sera, and blister fluids of SJS/TEN patients were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay. NLRP3 formation and CD8⁺ T cell activation status and their functions were examined by immunoblotting, immunofluorescence, and chemotaxis assays.

Results: The expression of the NLRP3 inflammasome complex was greatly increased in skin lesions of SJS/TEN patients. Moreover, IL-1β and IL-18 levels in sera and blister fluids of SJS/TEN patients were approximately 3-fold higher than those in healthy individuals, with a linear correlation between IL-1β levels and disease activity. CBZE induced NLRP3 inflammasome formation, upregulated CXCL9/CXCL10 levels, and activated CD8⁺ cytotoxic T cell functions via IL-1β/IL-1R or IL-18/IL-18R signaling in SJS/TEN keratinocytes, which promoted CD8⁺ cytotoxic T cell migration in SJS/TEN patients.

Conclusion: This study showed that CBZE promoted NLRP3 inflammasome formation and strengthened the activation and function of CD8⁺ cytotoxic T cells in the skin, which contributed to the initiation and progression of SJS/TEN.