title: Methylthioadenosine reprograms macrophage activation through adenosine receptor stimulation.
abstract: Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNFα production following LPS stimulation. We found that MTA could block TNFα production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1β production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Biological Sciences, Texas Tech University, Lubbock, Texas, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Keyel
authors.affiliation: Department of Biological Sciences, Texas Tech University, Lubbock, Texas, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Biological Sciences, Texas Tech University, Lubbock, Texas, United States of America.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kwak
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Salter
mesh_terms: D000818:Animals; D003839:Deoxyadenosines / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013872:Thionucleosides / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D003839:Deoxyadenosines; D053583:Interleukin-1beta; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D013872:Thionucleosides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C008500:5'-methylthioadenosine