Graduate Research Associate The Ohio State University Columbus, Ohio, United States
Background: After tissue injury, stressed cells release “damage associated molecular pattern” (DAMP) proteins normally found within the intracellular environment that serve as ligands to cell surface receptors. S100A9 is a bona fide DAMP found normally within macrophages that functions in a multitude of inflammatory responses, including activation of the Toll-like receptor 4 (TLR4). We hypothesized that PIPN, a debilitating TLR4-dependent toxicity, is mediated via S100A9. Methods: In vivo studies were performed with paclitaxel in wild-type and S100A9(-/-) mice and animals receiving genetic bone-marrow transplants. Gene and protein expression, electrophysiology, and behavioral tests (Von Frey hair) were recorded pre- and post-treatment. Pharmacokinetic profiling was performed with LC-MS/MS-based methods. Results: Paclitaxel caused dramatic upregulation of S100A9 expression in neurons and induced acute or chronic PIPN in wild-type mice (p < 0.05) but not S100A9(-/-) mice. Transplantation of S100A9(-/-)-bone marrow into wild-type mice or treatment with the S100A9 inhibitor tasquinimod also provided protection against PIPN. Genetic deficiency of S100A9 or treatment with tasquinimod did not influence paclitaxel pharmacokinetics (p>0.05). Conclusion: We have identified the DAMP protein S100A9 as a key mediator of PIPN that originates from recruitment of bone marrow-derived macrophages into the peripheral nervous system. This signaling cascade is activated upon a paclitaxel-mediated injurious event and is highly sensitive to targeting with a small-molecule S100A9 inhibitor without causing pharmacokinetic drug-drug interactions. The utility of S100A9 inhibitors as a therapeutic strategy to ameliorate PIPN is currently under investigation in tumor-bearing models.
