Inflammation-associated Autophagy Dysfunction

Chronic TNF-driven inflammation and deregulated hemostasis are characteristic of sickle cell disease (SCD). Despite TNFα's pivotal role in the pathophysiology of SCD and its role in deregulating hemostasis in other inflammatory diseases, the precise mechanisms by which it disrupts the hemostatic balance in SCD remain poorly understood. In response to TNFα, platelets accumulate larger amounts of mitochondria. Such modification is paralleled by functional changes that deregulate platelets' hemostatic role. More recently, it has been demonstrated that in SCD, a proportion of mature red blood cells (RBCs) contain dysfunctional mitochondria that promote hemolysis. Given that both RBCs and platelets originate from common hematopoietic precursors (Megakaryocytic Erythroid Progenitors), TNFα may disrupt common regulatory pathways in platelets and erythroid cells responsible for the clearance of mitochondria. Hence, we hypothesize that TNF-driven inflammation in SCD blocks autophagy and mitophagy in platelets and reticulocytes, 1) leading to the accumulation of dysfunctional mitochondria and deregulation of platelet’s hemostatic function and 2) disrupting the clearance of mitochondria by reticulocytes that consequently generate mature RBCs with retained mitochondria. Our long- term goal is to identify inflammation-mediated mechanisms that disrupt autophagy in platelets and erythroid cells in SCD. Ultimately, we aim to develop novel therapies to effectively address these pathophysiological aspects of the disease. Project Number: 1R00HL177831-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Pavel Davizon-Castillo | Institution: BLOODWORKS, SEATTLE, WA | Award Amount: $465,000 | Activity Code: R00 | Study Section: Special Emphasis Panel[ZHL1 CSR-N (O1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R00HL17783101