MUC1 and SIGIRR as Negative Regulators of TLR Signaling: Expression, Function, and Anti-inflammatory Augmentation

Toll-like receptors (TLRs) play a key role in initiating innate and acquired immunity, but their overactivation is also implicated in the development of autoimmune and chronic inflammatory conditions. To ensure tight regulation of TLR signaling, it is crucial to understand the expression and function of negative regulators of TLR signaling, such as mucin-1 (MUC1) and single immunoglobulin interleukin-1-related receptor (SIGIRR). Given these aspects, my research has revealed the following findings. 1) Membrane-tethered mucin glycoprotein MUC1 suppresses various TLR signaling pathways via its intracellular domain. 2) Lipopolysaccharide (LPS)-TLR4-p38 pathway suppresses SIGIRR gene expression. 3) Dominant-negative mutant of SIGIRR (Δ8-SIGIRR) reduces cell surface expression of wild-type SIGIRR in airway epithelial cells derived from cystic fibrosis (CF), characterized by chronic lung inflammation. The reduction of SIGIRR disrupts the SIGIRR/interleukin-18 receptor α (IL-18Rα) complex formation with interleukin-37 (IL-37), resulting in the impairment of the diverse anti-inflammatory activities of IL-37. 4) Enhancement of anti-inflammatory pathway via induction of SIGIRR/IL-18Rα expression and interaction. In CF cells, inhibition of histone deacetylase 3 (HDAC3) induces SIGIRR and IL-18Rα expression and restores IL-37-dependent anti-inflammatory responsiveness. To identify compounds as alternatives to IL-37, we developed a novel screening system capable of detecting SIGIRR/IL-18Rα heterodimer formation. Using this system, we discovered natural compounds that promote the interaction between SIGIRR and IL-18Rα. These findings provide fundamental insights into the treatment of inflammatory diseases and highlight the potential of MUC1 and SIGIRR as promising therapeutic targets.