Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren’s syndrome prior to disease onset

• Published in: Immunology and cell biology Vol. 87; no. 1; pp. 81 - 90
• Main Authors: Bulosan, Marievic, Pauley, Kaleb, Yo, Kyumee, Chan, Edward K., Katz, Joseph, Peck, Ammon B., Cha, Seunghee
• Format: Journal Article
• Language: English
• Published: 21.10.2008
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2008.70

To date, little is known why exocrine glands are subject to immune cell infiltrations in Sjögren’s syndrome (SjS). Studies with SjS-prone-C57BL/6.NOD- Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks prior to disease onset and suggested potential involvement of inflammatory caspases (caspases-11 and -1). To determine if inflammatory caspases are critical for the increased epithelial cell death prior to SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent up-regulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity, and apoptotic epithelial cells in the SMX of C57BL/6.NOD- Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for IL-1β and IL-18 secretion, resulted in elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD- Aec1Aec2 were not co-localized with caspase-11, indicating that caspase-11 functions in a non-cell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of LPS-and IFN-γ-stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset.