Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

Abstract

Telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that inhibit several proinflammatory and Th1-biased immune responses. Synthetic oligodeoxynucleotides (ODN) expressing suppressive motifs can reproduce the down-regulatory activity of mammalian telomeric repeats and have proven effective in the prevention and treatment of several autoimmune and autoinflammatory diseases. Endotoxin-induced uveitis (EIU) is an established animal model of acute ocular inflammation induced by LPS administration. Augmented expression of proinflammatory cytokines/chemokines such as TNF␣, IL-6, and MCP1 and bactericidal nitric oxide production mediated by LPS contribute to the development of EIU. Suppressing these mediators using agents that are devoid of undesirable systemic side effects may help prevent the development of EIU. This study demonstrates the selective down-regulatory role of suppressive ODN after (i) local or (ii) systemic treatment in EIU-induced rabbits and mice. Our results indicate that suppressive ODN down-regulate at both the transcript and protein levels of several proinflammatory cytokines and chemokines as well as nitric oxide and co-stimulatory surface marker molecules when administrated prior to, simultaneously with, or even after LPS challenge, thereby significantly reducing ocular inflammation in both rabbit and mouse eyes. These findings strongly suggest that suppressive ODN is a potent candidate for the prevention of uveitis and could be applied as a novel DNAbased immunoregulatory agent to control other autoimmune or autoinflammatory diseases.DNA and RNA are the essential components of all living organisms. Accumulated evidence strongly suggests that these nucleic acids have multiple and complex effects on the immune system and are more than a blueprint of life (1, 2). On one hand, due to their high unmethylated CpG motif frequency, bacterial DNAs are recognized as "non-self" via TLR9 (Toll-like receptor 9) and trigger an innate immune response characterized by the proliferation and maturation of B cells, natural killer cells, and plasmacytoid dendritic cells and the secretion of T-helper 1-type cytokines, chemokines, and/or multivalent immunoglobulins (3-8). On the other hand, telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that can inhibit several TLR-dependent and TLR-independent Th1-mediated immune responses. Of note, these motifs are underrepresented in the prokaryotic genome. Synthetic singlestranded oligodeoxynucleotides (ODN) 3 containing repetitive TTAGGG motifs mimic this effect (1, 9 -11). Previous studies revealed that deleterious inflammatory responses to a host can be down-regulated by suppressive ODN. In vitro, suppressive ODN inhibits the production of several proinflammatory cytokines and chemokines induced by bacteria (1,(12)(13)(14). Furthermore, in vivo suppressive ODN administration reduces the frequency and severity of several autoimmune and inflammatory diseases such as arthritis, systemic lupus erythematosus, pulmonary inflam...

Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides

“…Three different models of autoimmune uveitis were examined: acute, recurrent, and persistent. In each case, treatment with A151 significantly reduced the magnitude of ocular inflammation and subsequent tissue damage [3,35,36].…”

“…Nucleic acids are the “blueprint of life” and thus essential components of all living organisms. DNA and RNA also have multiple and complex effects on the immune system [1–3]. The nucleic acids present in pathogenic microorganisms can trigger toll-like receptors on immune cells, stimulating them to mount a protective response [4–9].…”

Anti-Inflammatory Mechanisms of the Annexin A1 Protein and Its Mimetic Peptide Ac2-26 in Models of Ocular Inflammation In Vivo and In Vitro

“…WT (n = 3) and AnxA1 2/2 (n = 3) mice were injected i.p. with 100 mg LPS in 200 ml PBS to induce EIU (29) and were sacrificed after 24 h; other WT (n = 3) and AnxA1 2/2 mice (n = 3) were not treated (naive groups).…”

Comparison of the clinical effects of Prednisolone, Azathioprine and Oligodeoxynucleotide (ODN) applications in experimentally induced endotoxin uveitis in rat

“…Uveitis is an ocular disease that is frequently encountered in clinics and leads to blindness as a result of damage to the uveal canal (iris, corpus ciliare, choroid) (Tian et al, 2015). It is characterized by ocular inflammation that can be formed in acute, recurrent, or persistent phases resulting from deterioration of the blood-ocular barrier and leukocyte infiltration (Yagci et al, 2010). Anatomically, it is classified as an anterior, intermediate, and posterior or panuveitis (Bansal et al, 2015).…”

“…The telomeric regions of mammalian chromosomes contain some proinflammatory and suppressive TTAGGG motifs that suppress Th1-based immunoreactivity. Synthetic oligodeoxynucleotides (ODN) suppressive motif expression has been shown to reduce the activation of telomeric repeats in mammals and has been shown to be effective in the prevention and treatment of some autoimmune and autoinflammatory diseases (Yagci et al, 2010).…”