Toll-like receptor (TLR) family members, TLR 3, 7 and 9, have been implicated in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During SLE progression these receptors are though to recognize self nucleic acids as well as self nucleic acid complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels. Recent studies have shown that inhibition of one or two nucleic-acid sensing TLRs using receptor antagonists can partially attenuate autoimmune disease progression. For example, inhibition of TLR7 and 9 results in reduced inflammation and glomerulonephritis, a hallmark of SLE. Current therapies are targeting nucleic-acid sensing TLRs as an effective way to control SLE induction and progression. However, these therapies may produce adverse long-term effects on immune responses and block the ability of immune cells to recognize foreign pathogens and adequately control the spread of infection. Thus, the most effective way to block TLR activation would be to control the ability of nucleic acid ligands to bind TLRs. We hypothesize that agents that bind to DNAs and RNAs regardless of their sequence, structure or chemistry might be able to act as molecular scavengers and inhibit nucleic acid-mediated activation of all RNA and DNA sensing TLRs. To test our hypothesis we propose to explore the potential utility of nucleic acid binding polymers as anti-inflammatory agents in the context of SLE. The overall goal of this proposal is to explore the mechanisms by which individual polymers block the ability of immune cells to produce cytokines post TLR activation, as well as determine the ability of these polymers to be used as therapeutic agents in prevention of SLE. Firstly, we will determine whether polymers are capable of blocking inflammatory processes, induced by TLR agonists, without affecting basic immune cell function. Furthermore, we will use two different approaches, cellular localization via confocal microscopy and TLR binding via surface plasmic resonance technology, to define the mechanism of action for the polymers tested. In addition, we will test the ability of polymers to be used as therapeutic agents in ameliorating chronic autoimmune diseases via two studies. First we will test the ability of polymers to block skin inflammation. We will then determine whether polymers are capable of preventing or reversing SLE. The successful completion of this project will provide us with valuable, potent, and well-characterized anti-inflammatory agents, which will block aberrant activation of immune cells during autoimmune disease development and progression.
A better understating of the mechanisms by which polymers inhibit inflammation that subsequently contributes to the development of autoimmune disorders will provide better insights for the prevention and/or treatment of these diseases. Successful completion of these goals may support the addition of polymers to the list of agents that are currently being considered as potential autoimmune disease drugs by multiple pharmaceutical companies.
|Holl, Eda K; Shumansky, Kara L; Borst, Luke B et al. (2016) Scavenging nucleic acid debris to combat autoimmunity and infectious disease. Proc Natl Acad Sci U S A 113:9728-33|
|Holl, Eda K; Bond, Jennifer E; Selim, Maria A et al. (2014) The nucleic acid scavenger polyamidoamine third-generation dendrimer inhibits fibroblast activation and granulation tissue contraction. Plast Reconstr Surg 134:420e-33e|
|Holl, Eda K (2013) Generation of bone marrow and fetal liver chimeric mice. Methods Mol Biol 1032:315-21|
|Holl, Eda K; Shumansky, Kara L; Pitoc, George et al. (2013) Nucleic acid scavenging polymers inhibit extracellular DNA-mediated innate immune activation without inhibiting anti-viral responses. PLoS One 8:e69413|
|Roney, Kelly; Holl, Eda; Ting, Jenny (2013) Immune plexins and semaphorins: old proteins, new immune functions. Protein Cell 4:17-26|