Abstract
Mimicking bacterial DNA, synthetic CpG-containing oligodeoxyribonucleotides (CpG-ODNs) have a powerful immunomodulatory potential. Their practical application is mainly associated with the production of vaccines, where they are used as adjuvants, as well as in local antimicrobial therapy. CpG-ODNs act on a wide variety of immune cells, including neutrophilic granulocytes. On the one hand, the stimulatory effect provides both the direct implementation of their antimicrobial and fungicidal mechanisms, and an avalanche-like strengthening of the immune signal due to interaction with other participants in the immune process. On the other hand, hyperactivation of neutrophilic granulocytes can have negative consequences. In particular, the formation of unreasonably high amounts of reactive oxygen species leads to tissue damages and, as a consequence, a spontaneous aggravation and prolongation of the inflammatory process. Under physiological conditions, a large number of DNA fragments are present in inflammation foci: both of microbial and self-tissue origin. We investigated effects of several short modified hexanucleotides on the main indicators of neutrophil activation, as well as their influence on the immunomodulatory activity of known synthetic CpG-ODNs. The results obtained show that short oligonucleotides partially inhibit the prooxidant effect of synthetic CpG-ODNs without significantly affecting the ability of the latter to overcome bacteria-induced pro-survival effects on neutrophilic granulocytes.
Highlights
Several decades have passed since convincing evidence was provided for the essential role of bacterial DNAs and the synthetic oligodeoxyribonucleotides (ODNs) mimicking them in the formation of the immune response
In order to search for opportunities to control the stimulating potential of synthetic oligonucleotides, we investigated the joint effects of CpG-ODNs and short hexanucleotides on PMNL functions
We analyzed the production of reactive oxygen species, adhesiveness, and apoptosis of neutrophilic granulocytes, that is, physiological responses that are most significant for the potentiation and timely resolution of the inflammatory response
Summary
Several decades have passed since convincing evidence was provided for the essential role of bacterial DNAs and the synthetic oligodeoxyribonucleotides (ODNs) mimicking them in the formation of the immune response. During this period, it became known that the presence of unmethylated CpG-motif is necessary for the successful activation of lymphocytes [1]. The Toll-like receptor 9 (TLR9) plays the most significant role in the recognition and initiation of the cellular response to bacterial DNA, host-derived denatured DNA fragments, and their synthetic analogs [5] This receptor is widely expressed and regulates the activity of immunocompetent cells, including neutrophilic granulocytes (or polymorphonuclear leukocytes, PMNLs). Systemic side effects can be associated with ROS-related vascular dysfunctions
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