An HDAC6 Inhibitor Confers Protection and Selectively Inhibits B-Cell Infiltration in DSS-Induced Colitis in Mice.
Small molecule histone deacetylase (HDAC) inhibitors with anti-inflammatory activity may be candidates for targeting intestinal inflammatory pathways in inflammatory bowel disease (IBD). This study investigated whether treatment with a potent HDAC6 inhibitor, BML-281, could protect against colonic inflammation and prevent inflammatory cell infiltration into the colon to drive disease pathology in a mouse model of acute dextran sodium sulfate (DSS) colitis. Control and acute DSS-colitis mice were treated with BML-281 (1 mg/kg per day s.c. and 10 mg/kg per day s.c.) for 8 days. Changes in disease pathology, colonic structure, function, alterations in inflammatory milieu, together with colonic inflammatory cell flux, were assessed by weight loss and disease activity index in vivo and by flow cytometry, gene expression, and histology ex vivo. Anti-inflammatory responses of BML-281 on human polymorphonuclear leukocytes were assessed in vitro. Administration of BML-281 to DSS-treated mice attenuated colitis, weight loss, and disease pathology, including changes in colon structure and function, by eliciting broad-spectrum anti-inflammatory effects and preventing infiltration and activation of key immune cells in the lamina propria of the intestinal epithelium. Among different immune cells, BML-281 particularly suppressed the infiltration of CD19+B-cells into the inflamed colonic lamina propria. This study supports the targeting of HDAC6 as an anti-inflammatory strategy for treating colon inflammation progressing to IBD. Some HDAC inhibitors are used in the clinic to treat cancer, and the results here for BML-281 highlight the potential for HDAC6 inhibitors to be used in a clinical setting for preventing and treating colonic inflammation and IBD in humans.
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia.
Anh
A
Do
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia.
Robert C
RC
Reid
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia.
Rink-Jan
RJ
Lohman
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia.
Matthew J
MJ
Sweet
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia a.iyer@imb.uq.edu.au d.fairlie@imb.uq.edu.au.
David P
DP
Fairlie
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia a.iyer@imb.uq.edu.au d.fairlie@imb.uq.edu.au.
Abishek
A
Iyer
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology*; D003967:Diarrhea / Q000150:complications; D005260:Female; D006470:Hemorrhage / Q000150:complications; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D018375:Neutrophil Activation / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism
C000619414:BML-281; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007555:Isoxazoles; D009077:Mucins; D016264:Dextran Sulfate; D009195:Peroxidase; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases