Targeting Macrophage Populations to Attenuate Pulmonary Hypertension Associated with Sickle Cell Disease

Sickle Cell Disease (SCD) is a genetic mutation that leads to hemoglobin (Hb) polymerization within the red blood cell (RBC), causing the characteristic sickle shape and subsequent hemolysis. Approximately 5-10% of the SCD population suffers from pulmonary hypertension compared to 1 in 3 million in the general population. The 5-year survival rate of SCD patients with PH is ~32%, higher than SCD patients without PH (~16%). A leading hypothesis for why the SCD patient population has such a greater prevalence of PH is that iron toxicity caused from hemoglobin or heme released during RBC hemolysis drives vascular lung injury and inflammation as observed by iron accumulation within the lungs of PH SCD patients. Iron accumulation stimulates an inflammatory cascaded leading to chronic inflammatory conditions within the lung microenvironment. Within chronic inflammatory diseases, such as PH and SCD, a disorganized area of adaptive and innate immune cells amasses in the lung as tertiary lymphoid structures. A critical cell type for adaptive immune cell (B and T cells) activation is the CD169+ macrophage found within the tertiary structure. Classically, these macrophages surround B and T cell areas within the spleen and lymph nodes, providing crucial support and cross talk for adaptive immune system activation. Thus, our overall hypothesize of this proposal is CD169+ macrophages are critical for PH disease progression in SCD. This hypothesis will be tested in three aims. Aim 1 will determine if targeting iron release from the ferroportin transporter modify CD169+ macrophage and adaptive immune cell quantities, phenotypes by multi-omics analysis, and oxidative status. Aim 2 will determine if ablation of CD169+ inhibits PH disease progression by altering the quantity and phenotype of adaptive immune cells within the lung, as determined by flow cytometry, multi-omics approach, and electron paramagnetic resonance. Aim 3 will determine if CD169+ macrophages are critical for adaptive immune cell recruitment to the lung microenvironment. Together, these aims will emphasize the importance of a specific cell type and allow for future projects and therapeutic targets with SCD PH. Receiving this award would drastically improve my career path towards independent research at the University of Colorado Anschutz Medical Campus. Project Number: 1K99HL177608-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Christina Lisk | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $111,626 | Activity Code: K99 | Study Section: NHLBI Mentored Transition to Independence Study Section[MTI (OA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL17760801