Scavenging nucleic acid debris to combat autoimmunity and infectious disease

Abstract

Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis

“…For example, although it is known that polycationic dendrimers such as PAMAM-G3 are primarily cleared by the liver and kidney and can be toxic to these organs, 46 the toxicity of these polymers is dosage dependent and the maximum tolerated in vivo doses of PAMAM-G3 in prior murine studies were reportedly up to 1,000 mg/kg, 50 times higher than the efficacious dose used in our current study and previous studies in other disease models. 5,46,57 Thus, the dosages of PAMAM-G3 needed to inhibit metastatic spread in the presented model of PC are well within the limits of the maximally tolerated dose. Furthermore, herein we show that healthy non-tumor-bearing mice treated with the same PAMAM-G3 dosing scheme displayed no laboratory abnormalities in hepatic or renal function or other common clinical markers over the duration of the study, suggesting that the NABP was well-tolerated.…”

Toll-Like Receptor Signaling in Burn Wound Healing and Scarring

“…39 Both nDNA and mtDNA can activate TLRs, and condensed complexes of these self-DNAs with proteins such as histones, HMGB1, and LL-37 can protect them from nucleases and may be crucial for their delivery to endosomes and TLR9 (discussed in 40 ). 41 In addition, another DAMP, decorin, was elevated in patient serum for 2 weeks after burn injury, correlated with TBSA, and predicted hypertrophic scar better than burn size. 2 Decorin is a small leucine-rich proteoglycan that can activate TLR4 (and downstream p38, extracellular signalregulated kinase [ERK], and NF-jB pathways) and lead to increased secretion of TNF-a, pro-IL-1b, and leukocyte chemoattractants.…”

Tuned Cationic Dendronized Polymer: Molecular Scavenger for Rheumatoid Arthritis Treatment

“…demonstrated that cationic polymers could be applied to scavenge the artificial proinflammatory nucleic acids and rescue mice from liver failure. Holl et al . proved that introduction of cationic polymers could limit autoimmunity caused by the endogenous cfDNA in lupus‐prone mice.…”

“…[1] Although TLR antagonists can reduce the cfDNA-induced inflammation, [2] inhibiting function of the TLR could result in immune suppression and adverse side effects,s uch as increased risk of infection. Lee et al [3] demonstrated that cationic polymers could be applied to scavenge the artificial proinflammatory nucleic acids and rescue mice from liver failure.H oll et al [4] proved that introduction of cationic polymers could limit autoimmunity caused by the endogenous cfDNAi nl upus-prone mice. Therefore,s cavenging nucleic acids (NAs) with cationic polymers may become an ew strategy to treat some immune diseases.However,most of the current cationic polymers for gene delivery may not be perfect cationic molecular scavengers of cfDNAb ecause they serve different purposes.…”