Cationic Cyclodextrins Regulate Nucleic Acid-induced Proinflammatory Responses

Abstract

Cyclodextrins (CDs) were discovered over a century ago for their ability to complex with several macromolecules and have found use in pharmaceutical industry to enhance solubility of drugs. Cationic CDs can bind nucleic acids (NA) and are being tested for delivery of NA to cells. Extracellular NAs can act as pro-inflammatory triggers and their inefficient clearance may activate Toll-like receptors (TLR) and contribute to autoimmune diseases such as lupus. We hypothesized that NA-binding CD (NABCD) may be used for scavenging extra-cellular NA to prevent pro-inflammatory responses. Here we investigated whether NABCD can modulate immune activation triggered by DNA or NA-TLR ligands. Indeed, in vitro assays using bone marrow derived macrophages (BMM) showed that NABCD induced a statistically significant inhibition of the expression of innate immune activation genes including Mx1, Prkr, Il1b and Tnfa when exposed to DNA or poly I:C. Treatment of C57BL/6 mice with TLR ligand polyI:C induced an acute pro-inflammatory response indicated by upregulation of interferon response genes and cytokine production. Treatment with NABCD not-only attenuated the innate-immune activation, but also modulated the adaptive immune response by significantly preventing a Th1 skewing of the immune response. The NABCD-treated mice also had higher numbers of IL-10 producing CD4 T-cells and more Foxp3+T-regulatory cells in the spleens as compared to mice treated only with polyI:C. Our data indicate a feasibility for the use of NABCD for modulating NA-induced proinflammatory responses and may find applications for treatment of autoimmune diseases such as lupus, where extra-cellular DNA plays a pathogenic role.