Kristina N. Fenner - PhD Candidate, Toxicology PhD Program
Hematopoietic stem and progenitor cells (HSPCs) differentiate into all of the mature cells of the blood in a process called hematopoiesis. Hematopoiesis is complex in that it is influenced by cell-intrinsic and extrinsic factors, which maintain the appropriate output of erythrocytes, leukocytes and platelets. External stressors, such as injury or infection, trigger HSPCs to change the production of blood cells, often called emergency hematopoiesis. This ability to sense and rapidly respond is essential for maintaining appropriate blood cell numbers; yet, the mechanisms that control emergency hematopoiesis are multifaceted and stressor-dependent. Environmental contaminants are one type of external stressor, and their influence on emergency hematopoiesis remains elusive. The aryl hydrocarbon receptor (AHR) is an environment-sensing intracellular receptor that binds a wide range of synthetic and naturally-derived small molecules. Experimental studies have shown that AHR modulation influences steady-state hematopoiesis, while other studies indicate that AHR ligands influence immune responses to infection. Collectively, these studies suggest that AHR could regulate emergency hematopoiesis; however, this has not been determined. Using several approaches, including exposing mice to the AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and infection with either a mouse coronavirus (CoV) or a human influenza A virus (IAV), we observed that AHR activation altered multiple aspects of emergency hematopoiesis. During infection with CoV or IAV, AHR activation skewed the proportion of primitive HPSCs and downstream hematopoietic progenitor cells in the bone marrow. These changes were accompanied with altered numbers of mature immune cells in the lung and blood. Furthermore, studies using conditional AHR knockout mice, which lack AHR in hematopoietic cells, showed that AHR expression in hematopoietic cells is necessary to affect emergency hematopoiesis. Also, AHR-mediated alterations to emergency hematopoiesis required AHR to have a functional DNA binding domain (DBD), which suggests AHR likely regulates emergency hematopoiesis by acting as a direct transcriptional regulator. Overall, these data provide novel evidence that AHR activation influences emergency hematopoiesis during respiratory viral infections, further supporting that AHR is a key mediator of hematopoiesis. This work has broad-reaching applications as dysregulated hematopoiesis is linked to the pathology of many diseases such as hematopoietic cancers, severe infections, and autoimmune diseases.
Jul 02, 2024 @ 1:00 p.m.
Medical Center | K-207 (2-6408)
Hybrid EventHost: Advisor: B. Paige Lawrence, PhD