Neutrophils: Novel contributors to estrogen-dependent intracranial aneurysm rupture via neutrophil extracellular traps

Title : Neutrophils: Novel contributors to estrogen-dependent intracranial aneurysm rupture via neutrophil extracellular traps

Abstract:

Background: Intracranial aneurysms (IAs) are more prevalent in women than men and aneurysmal subarachnoid hemorrhage disproportionately affects postmenopausal women. These sex differences suggest estrogen protects against IA progression that can lead to rupture, but the underlying mechanisms are not fully understood. Although studies have demonstrated estrogen regulates inflammatory processes that contribute to IA pathogenesis, the role of neutrophils remains to be characterized. Using a murine model, we tested our hypothesis that neutrophils contribute to IA pathophysiology in an estrogen-dependent manner.   

Methods: We compared neutrophil infiltration in C57BL/6 mice that develop IAs to those with a normal circle of Willis. Next, we investigated the role of neutrophils in estrogen-deficient female mice, estrogen-deficient female mice treated with estrogen rescue, and male mice using a neutrophil depletion antibody. Finally, we studied the role of neutrophil extracellular trap formation (NETosis) as an underlying mechanism of aneurysm progression. 

Results: Mice that developed aneurysms had increased neutrophil infiltration compared to those with a normal circle of Willis. In estrogen-deficient female mice, both neutrophil depletion and NETosis inhibition decreased aneurysm rupture. In estrogen-deficient female mice treated with estrogen rescue and estrogen-intact female mice, neither neutrophil depletion nor NETosis inhibition affected IA formation, rupture, or symptom-free survival. In male mice, neutrophil depletion decreased IA formation and improved symptom-free survival but did not affect rupture. NETosis inhibition in male mice did not affect IA formation, rupture, or symptom-free survival.  

Conclusion: Neutrophils contribute to aneurysm rupture in an estrogen-dependent manner. NETosis appears to be an underlying mechanism for neutrophil-mediated IA rupture in estrogen deficiency. Targeting NETosis may lead to the development of novel therapeutics to protect against IA rupture in the setting of estrogen deficiency.

Biography:

Brandon Lucke-Wold was born and raised in Colorado Springs, CO. He graduated magna cum laude with a BS in Neuroscience and distinction in honors from Baylor University. He completed his MD/PhD, Master’s in Clinical and Translational Research, and the Global Health Track at West Virginia University School of Medicine. His research focus was on traumatic brain injury, neurosurgical simulation, and stroke. At West Virginia University, he also served as a health coach for the Diabetes Prevention and Management program in Morgantown and Charleston, WV, which significantly improved health outcomes for participants. In addition to his research and public health projects, he is a co-founder of the biotechnology company Wright-Wold Scientific, the pharmaceutical company CTE cure, and was a science advocate on Capitol Hill through the Washington Fellow’s program. 

He has also served as president of the WVU chapters for the American Association of Pharmaceutical Scientists, Neurosurgery Interest group, and Erlenmeyer Initiative Entrepreneur group. In addition, he has served as vice president for the graduate student neuroscience interest group, Nu Rho Psi Honor Society, and medical students for global health. He was an active member of the Gold Humanism Honor Society and Alpha Omega Alpha Honor Society. He is currently a member of the UF House Staff Council, Positive Culture Committee, Quality Improvement Committee, Board of Directors Alachua County Medical Society, and Accreditation Requirements Review Committee. He is married to Noelle Lucke-Wold and has two children.  As a family, they enjoy running with their dogs, rock climbing, and traveling.  In his spare time, Brandon frequently runs half marathons and 10ks together with is wife. Brandon also enjoys reading, playing piano, discussing philosophy, and playing chess. He is currently a Pgy5 neurosurgery resident at University of Florida with pursuing endovascular enfolded training and was awarded the Dempsey Cerebrovascular Research Fellowship.