EVIDENCE for the DIFFERENTIAL SUBORDINATION of the IL-18 / IFNΥ AXIS to CASPASE-1 AMONG PATIENTS with CROHN’S DISEASE

In Crohn’s disease (CD), hierarchical architecture of the inflammatory network, including subordination of IL-18, an IFNΥ-inducing cytokine, to the inflammasome, have remained undeciphered. Heterogeneity among patients of such a subordination cannot be evaluated by animal models, monofactorial in their etiology and homogenous in disease progression. To address these issues, we setup an ex vivo model of inflamed mucosa explant cultures from full-blown CD patients. Th1 cytokine production, especially IFNΥ and IL-18, was assessed in relation with inflammation intensity. Subordination of the Th1 response to caspase-1, effector of the inflammasome, was determined in explant cultures subjected to pharmacological inhibition of caspase-1. We showed a correlation between secreted IFNΥ / IL-18 levels, and caspase-1 activation, with inflammation intensity of intestinal CD mucosa. Inhibition of caspase-1 activation using the specific inhibitor YVAD identified a homogenous non responder group featuring a caspase-1-independent IL-18 / IFNΥ response, and a heterogenous responder group, in which both IL-18 and IFNg responses were caspase-1-dependent (40% - 70% inhibition by YVAD). These findings bring out the concept of heterogeneity of subordination of the Th1 response to inflammasome activation among CD patients. This ex vivo model should have therapeutic relevance in allowing to determine eligibility of CD patients for new targeted therapies.