NLRP3-Dependent and -Independent Processing of Interleukin (IL)-1β in Active Ulcerative Colitis

A contributing factor in the development of ulcerative colitis (UC) and Crohn's disease (CD) is the disruption of innate and adaptive signaling pathways due to aberrant cytokine production. The cytokine, interleukin (IL)-1 beta, is highly inflammatory and its production is tightly regulated through transcriptional control and both inflammasome-dependent and inflammasome- independent proteolytic cleavage. In this study, qRT-PCR, immunohistochemistry, immunofluorescence confocal microscopy were used to (1) assess the mRNA expression of NLRP3, IL-1 beta, CASP1 and ASC in paired biopsies from UC and CD patient, and (2) the colonic localization and spatial relationship of NLRP3 and IL-1 beta in active and quiescent disease. NLRP3 and IL-1 beta were found to be upregulated in active UC and CD. During active disease, IL-1 beta was localized to the infiltrate of lamina propria immune cells, which contrasts with the near-exclusive epithelial cell layer expression during non-inflammatory conditions. In active disease, NLRP3 was consistently expressed within the neutrophils and other immune cells of the lamina propria and absent from the epithelial cell layer. The disparity in spatial localization of IL-1 beta and NLRP3, observed only in active UC, which is characterized by a neutrophil-dominated lamina propria cell population, implies inflammasome-independent processing of IL-1 beta. Consistent with other acute inflammatory conditions, these results suggest that blocking both caspase-1 and neutrophil-derived serine proteases may provide an additional therapeutic option for treating active UC.