Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Sulfasalazine and thalidomide inhibit extracellular trap formation by human neutrophils and mast cells

Investigator: Andrew Lin, University of Michigan Medical School

Mentor: Allen T. Bruce, MD, PhD, University of Michigan Medical School

Extracellular trap formation (ETosis) is a recently discovered form of cell death distinct from necrosis or apoptosis where a lattice of DNA strands is extruded from innate immune cells. Although ETosis is typically thought of as an antimicrobial response, recent work in our lab has shown that mast cells and neutrophils form IL-17+ extracellular traps (ET) in human psoriasis plaques but not in normal uninvolved skin. In autoinflammatory diseases, overproduction or insufficient clearance of ETs may lead to inappropriately sustained stimulation of the innate immune system. However, while several important treatments for psoriasis and other autoimmune diseases are known to inhibit T cells or cytokines such as TNF-a, IL-17, and IL-23, drugs that inhibit ETosis have not been identified. There are several drugs known to be effective in psoriasis and other autoimmune conditions that work through incompletely understood mechanisms of action. We hypothesized that the clinical effectiveness of some these drugs may be attributed in part to their inhibition of ETosis. Using neutrophils isolated from human donors and the human mast cell line, HMC-1, we investigated the effects of various drugs on ETosis. Using immunofluorescence and assays measuring extruded ET DNA, we found that sulfasalazine and thalidomide significantly inhibit ET formation in neutrophils and mast cells in a dose-dependent fashion. In contrast, cyclosporine, tacrolimus, tetracycline, colchicine, hydroxychloroquine, cromolyn, or dapsone had no significant effect on ETosis in these experiments. These studies demonstrate a previously unappreciated mechanism by which sulfasalazine and thalidomide can dampen the inflammatory response by decreasing neutrophil and mast cell activity. Inhibition of ETosis by these and other drugs may prove to be valuable clinically in the treatment of inflammatory conditions.

Updated on July 30, 2012.


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