BET inhibition blunts antibody production and macrophage-mediated fibrosis to restore lung function in murine cGVHD
Abstract
Abstract Chronic graft-versus-host disease (cGVHD) significantly contributes to late mortality after allogeneic stem cell transplantation, with bronchiolitis obliterans syndrome (BOS) being a particularly lethal and treatment-resistant complication despite available therapies. Bromodomain and extraterminal (BET) proteins are epigenetic readers driving inflammatory transcriptional programs across multiple cell types. We hypothesized that BET inhibition would suppress inflammatory T and B cells and decrease macrophage polarization to a profibrotic phenotype, alleviating disease. In an established BOS cGVHD model, BET inhibition reduced germinal center (GC) formation and responses through a reduction of the CXCL13:CXCR5 axis and inflammatory T follicular helper/GC B cells in the spleen, along with a reduction in plasma cell infiltration within the lung. Mice with cGVHD had elevated pathogenic immunoglobulin G1 (IgG1) and IgM levels, both in circulation and deposited on lung tissue, which were attenuated under BET inhibition. Single-cell RNA-sequencing analysis revealed distinct cell states in the BOS lung vs control. In cGVHD mice, gene set enrichment analysis revealed the upregulation of profibrotic Arginase1 and Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced with BET inhibition. Furthermore, BET inhibition targeted lung-infiltrating M2 macrophages through the selective depletion of CD206+FcγR+ IM and AM, ultimately resulting in reduced collagen deposition and improved lung function. Our findings reveal a previously unrecognized mechanistic axis of BET regulation during cGVHD fibrosis and highlight BET inhibition as a promising therapeutic strategy.
Article Details
Authors (25)
Rathan Kumar
The Ohio State University, Columbus, Ohio, United States
Lotus Neidemire-Colley
The Ohio State University, Columbus, Ohio, United States
Elizabeth A. R. Garfinkle
3Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH
Camryn Steere
The Ohio State University, COLUMBUS, Ohio, United States
Simran Surana
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Annie Murray
Giorgia Giordano
The Ohio State University, United States
Olivia Martin
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Emerson D. Woodbury
4Division of Cardiac Surgery, Department of Surgery, The Ohio State University, Columbus, OH
Adithe Rivaldi
Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Satishkumar Singh
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Kara Corps
Katlyn Lederer
6Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Malith Karunasiri
The Ohio State University, Columbus, Ohio, United States
Matthew W. Gorr
Loren E. Wold
Lalit Sehgal
Kenneth J. Oestreich
Nicole R. Grieselhuber
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Marcos J. de Lima
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Bruce R. Blazar
Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota
Ivan Maillard
Katherine E. Miller
Hannah K. Choe
1Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Parvathi Ranganathan
Ohio State University, Columbus, Ohio, United States