Eliana Andrea
Research Mentor: Jason Knight
Mentor Department: Internal Medicine/Rheumatology, Medicine
Author(s): Thalia Newman, Jason Knight
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 27
Abstract
Antiphospholipid Syndrome (APS) is a chronic autoimmune disease that promotes a thrombotic environment, leading patients to develop blood clots. The standard treatment for APS is lifelong anticoagulation. This approach fails to address the root cause of disease in APS patients, leading to inconsistencies in preventing thrombosis. Pathogenic antiphospholipid antibodies (aPL) activate neutrophils to form neutrophil extracellular traps (NETs) in a process known as NETosis. When formed in excess, NETs promote a pro-inflammatory and pro-thrombotic environment, highlighting NETosis as a novel therapeutic target in APS. We have previously shown that aPL trigger NETosis through Toll-like receptor 4 (TLR4) and that APS neutrophils upregulate TLR4-associated genes, including CD14 and the downstream MAP kinases (MAPKs) p38, ERK, and JNK. For this project, we wanted to investigate the dependence of APS-associated NETosis on the TLR4-relevant proteins CD14, p38, ERK, and JNK to identify novel therapeutic targets. Primary human neutrophils isolated from whole blood were treated with patient-derived aPL in the presence or absence of one of the following inhibitors: TAK-242 (TLR4), atibuclimab (CD14), adezmapimod (p38), SCH772984 (ERK), and SP600125 (JNK). After treatment, cell activation and NETosis were quantified to assess the dependency of aPL on the target proteins. Inhibition of CD14 strongly protected against aPL-induced neutrophil activation and NETosis. Inhibition of p38 and JNK protected cells from NETosis, but had more moderate impacts on activation. Inhibition of ERK had minimal benefit. These findings highlight the potential of CD14-dependent signaling as a novel therapeutic target for APS-associated NETosis. Continued work aims to determine the CD14 dependence of MAPK activation downstream of aPL.
