Blood Advances (May 2025)
PRMT5 inhibition reduces hyperinflammation in a murine model of secondary hemophagocytic lymphohistiocytosis
- Fiona Brown-Burke,
- Rachel Saadey,
- Hsiao-Yin Charlene Mao,
- Paola Marra,
- Eric Brooks,
- Alexa Wandtke,
- Ian Hout,
- Sydney Leon,
- Archisha Sharma,
- Aneeq Yasin,
- Taylor Cash,
- Elshafa Hassan Ahmed,
- Ethan Baiocchi,
- Stephanie Finoti,
- Xiaoli Zhang,
- Neha Bhagwat,
- Kris Vaddi,
- Peggy Scherle,
- Anna Mozhenkova,
- Ikbale El-Ayachi,
- Austin D. Schenk,
- Shelby L. Sloan,
- Kaylee Whitman,
- JoBeth Helmig-Mason,
- Sheldon Steyn,
- Haley L. Klimaszewski,
- Jessica Weist,
- Christoph Weigel,
- Shirsha Koirala,
- Lapo Alinari,
- Katiri Snyder,
- Parvathi Ranganathan,
- Chia-Jo Chen,
- Michael B. Jordan,
- Robert A. Baiocchi,
- Polina Shindiapina
Affiliations
- Fiona Brown-Burke
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Rachel Saadey
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Hsiao-Yin Charlene Mao
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Paola Marra
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Eric Brooks
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Alexa Wandtke
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Ian Hout
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Sydney Leon
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Archisha Sharma
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Aneeq Yasin
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Taylor Cash
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Elshafa Hassan Ahmed
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- Ethan Baiocchi
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Stephanie Finoti
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Xiaoli Zhang
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH
- Neha Bhagwat
- Prelude Therapeutics, Wilmington, DE
- Kris Vaddi
- Prelude Therapeutics, Wilmington, DE
- Peggy Scherle
- Prelude Therapeutics, Wilmington, DE
- Anna Mozhenkova
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Ikbale El-Ayachi
- Division of Transplantation Surgery, The Ohio State University Wexner Medical, Columbus, OH
- Austin D. Schenk
- Division of Transplantation Surgery, The Ohio State University Wexner Medical, Columbus, OH
- Shelby L. Sloan
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- Kaylee Whitman
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- JoBeth Helmig-Mason
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Sheldon Steyn
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Haley L. Klimaszewski
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Jessica Weist
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Christoph Weigel
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Shirsha Koirala
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Lapo Alinari
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Katiri Snyder
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Parvathi Ranganathan
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH
- Chia-Jo Chen
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
- Michael B. Jordan
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH
- Robert A. Baiocchi
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; Correspondence: Robert A. Baiocchi, Division of Hematology, College of Medicine, The Ohio State Univeristy, 400 W 12th Ave, 481A Wiseman Hall CCC, Columbus, OH 43210;
- Polina Shindiapina
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; Polina Shindiapina, Division of Hematology, College of Medicine, The Ohio State University, 400 W 12th Ave, 481E Wiseman Hall CCC, Columbus, OH 43210;
- DOI
- https://doi.org/10.1182/bloodadvances.2024013651
- Journal volume & issue
-
Vol. 9,
no. 10
pp. 2379 – 2392
Abstract
Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation and excessive production of proinflammatory cytokines leading to tissue damage and multisystem organ failure. There is an urgent need for the discovery of novel targets and development of therapeutic strategies to treat this rare but deadly syndrome. Protein arginine methyltransferase 5 (PRMT5) mediates T-cell–based inflammatory responses, making it a potential actionable target for the treatment of HLH. Using CPG-1826 and anti–interleukin-10R (IL-10R) antibody, we induced murine secondary HLH in vivo with a marked expansion of splenic myeloid cell subsets and concurrent reduction of T- and natural killer (NK)–cell populations. PRMT5 expression was significantly upregulated in splenic T and NK lymphocytes, monocytes, and dendritic cells in mice with HLH (P .999 for both). PRT382 treatment also reduced the expansion of myeloid cell populations (P < .0001) in mice with HLH, compared with untreated mice, while restoring T- and NK-cell numbers (P < .001 for both). These results identify PRMT5 as a promising target for the management of secondary HLH and justify further exploration in this and other models of hyperinflammation.
