title: TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses.
abstract: Sepsis is a highly fatal disease caused by an initial hyperinflammatory response followed by a state of profound immunosuppression. Although it is well appreciated that the initial production of proinflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that Toll-like receptor (TLR)-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of adenosine triphosphate (ATP). This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key "molecular switch" that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD;
authors.forename: Heather B
authors.initials: HB
authors.lastname: Cohen
authors.forename: Katharine T
authors.initials: KT
authors.lastname: Briggs
authors.forename: John P
authors.initials: JP
authors.lastname: Marino
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: David M
authors.initials: DM
authors.lastname: Mosser
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001081:Apyrase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen
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