Cardiometabolic Disease Enhances Basophil-Endothelium Interactions for Inflammation Resolution

Cardiometabolic diseases (CMD), including obesity, type II diabetes, and hypertension, are major contributors to global morbidity and mortality. Elevated levels of reactive oxygen species (ROS) and subsequent endothelial oxidative stress seen in these diseases promotes vascular dysfunction and chronic inflammation. The enzyme NADPH oxidase 4 (NOX4) constitutively produces hydrogen peroxide (H 2 O 2 ), a reactive oxygen species (ROS) necessary for a variety of intercellular signaling processes. Our preliminary data suggest that NOX4 upregulation of H 2 O 2 levels is correlated with increased production and subsequent release of basophils from hematopoietic sites such as the bone marrow and spleen. Basophils are traditionally known for their role in allergic reactions and parasitic infections, however, they are becoming increasingly recognized as important players in the inflammatory response associated with cardiometabolic diseases. Through activation of focal adhesion kinases (FAKs), basophils influence endothelial expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), promoting a pro-inflammatory endothelial phenotype. Further, it has been shown that basophil counts positively correlate with plasma coagulant activity and increased mortality in patients with coronary artery disease. These studies suggest a deleterious role for basophils during conditions associated with CMD. Thus, it is crucial to better understand the mechanisms underlying basophil activation and action upon endothelium during CMD, especially as endothelial dysfunction is a key feature of CMD that precedes many cardiovascular diseases. Given our preliminary observations that H 2 O 2 -producing NOX4 is upregulated in endothelial cells (ECs) during CMD, and that H 2 O 2 increases basophil production and activation, we hypothesize that oxidative stress exacerbates endothelial dysfunction via expansion and activation of basophils. We have found using in vitro murine bone marrow cultures that modulation of H 2 O 2 levels leads to differences in not only basophil proliferation, but also gene signatures related to inflammatory response pathways. Through single cell RNA-sequencing of basophils isolated from mice placed on a normal chow (NC) or high fat, high sucrose (HFHS; 40% kcal each) diet meant to mimic conditions of human CMDs, we have observed an expansion in basophil heterogeneity, activation signatures, and endothelial interacting genes in the HFHS diet fed mice. In accordance with cases of endothelial dysfunction driven by cardiometabolic diseases, our ongoing studies aim to reveal potential mechanisms behind this unique endothelial-immune interaction, providing new insights into the role of basophil-endothelial crosstalk in the pathogenesis of cardiometabolic diseases and the mechanisms driving chronic inflammation and vascular dysfunction. R01HL171997, R01HL137112, T32HL007284 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.