Multiple Immunosuppressive Effects of CpG-c41 on Intracellular TLR-Mediated Inflammation

Abstract

A growing body of literature suggests that most chronic autoimmune diseases are associated with inappropriate inflammation mediated by Toll-like receptor (TLR) 3, TLR7/8, or TLR9. Therefore, research into blocking TLR activation to treat these disorders has become a hot topic. Here, we report the immunomodulatory properties of a nonstimulatory CpG-containing oligodeoxynucleotide (CpG-ODN), CpG-c41, which had previously only been known as a TLR9 antagonist. In this study, we found that both in vitro and in vivo CpG-c41 decreased levels of various proinflammatory factors that were induced by single activation or coactivation of intracellular TLRs, but not membrane-bound TLRs, no matter what downstream signal pathways the TLRs depend on. Moreover, CpG-c41 attenuated excessive inflammation in the imiquimod-induced psoriasis-like mouse model of skin inflammation by suppressing immune cell infiltration and release of inflammatory factors. We also found evidence that the immunosuppressive effects of CpG-c41 on other intracellular TLRs are mediated by a TLR9-independent mechanism. These results suggest that CpG-c41 acts as an upstream of signaling cascades, perhaps on the processes of ligand internalization and transfer. Taken together, these results suggest that CpG-c41 disrupts various aspects of intracellular TLR activation and provides a deeper insight into the regulation of innate immunity.

CpG-Oligodeoxynucleotides Alleviate Tert-Butyl Hydroperoxide-Induced Macrophage Apoptosis by Regulating Mitochondrial Function and Suppressing ROS Production

“…Unmethylated CpG motifs, which are mostly presented in microbial DNA, are one of the factors involved in immune responses. Among the TLRs, TLR9 is the major participant in unmethylated CpG oligonucleotide recognition, and CpG ODN-induced TLR9 activation regulates immune cells and exerts anti-inflammatory effects [38][39][40][41].…”

Computational advances of tumor marker selection and sample classification in cancer proteomics

“…Clustering or unsupervised modeling is a powerful technique for discovering the molecular classification of patient’s cancer tissues [184] and identifying subtype specific characterization (e.g. subtype specific cancer therapeutic targets) [185] , [186] . The underlying theories of clustering technique are considering the similarities among different samples based on high dimension proteins or peptides, which can provide information of the same or differential patterns on protein expression level, aiming at clustering those biologically similar samples together [187] .…”

Emerging Mechanisms of Innate Immunity and Their Translational Potential in Inflammatory Bowel Disease

“…In vitro studies of the c41 ODN, from Pseudomonas aeruginosa , in a murine macrophage cell line and in human monocytes demonstrates that this sequence binds to TLR9 without triggering downstream cascades but prevents other ODNs from binding and so has uses as a TLR9 antagonist ( 265 ). A subsequent study demonstrated more diverse actions of c41 on TLR activation suggesting wider effects than simply TLR9 ( 266 ). Similar to c41, the antimalarial drug chloroquine has diverse effects on TLR signaling but particularly via TLR9 to alleviate murine colitis ( 267 ).…”