title: The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells.
abstract: Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors hypoxia-inducible factor 1α and nuclear factor κB (NF-κB) via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of hypoxia-inducible factor 1 and NF-κB. We have demonstrated in vivo that pretreatment with DMOG attenuates systemic LPS-induced activation of the NF-κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. Dimethyloxallyl glycine treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of proinflammatory cytokines such as TNF-α. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B1 cell population. This study demonstrates cell type-specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.
authors.affiliation: Institute of Molecular Medicine, Trinity College, Dublin, Ireland.
authors.forename: Emily
authors.initials: E
authors.lastname: Hams
authors.forename: Sean P
authors.initials: SP
authors.lastname: Saunders
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.forename: Aisling
authors.initials: A
authors.lastname: O'Connor
authors.forename: Murtaza T
authors.initials: MT
authors.lastname: Tambuwala
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.forename: Annette
authors.initials: A
authors.lastname: Byrne
authors.forename: Antonio
authors.initials: A
authors.lastname: Campos-Torres
authors.forename: Paul M
authors.initials: PM
authors.lastname: Moynagh
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000627:therapeutic use*; D000818:Animals; D005434:Flow Cytometry; D015151:Immunoblotting; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053701:Receptors, Interleukin-10 / Q000097:blood; D018805:Sepsis / Q000188:drug therapy; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000600:Amino Acids, Dicarboxylic; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D006899:Mixed Function Oxygenases; C040947:oxalylglycine