TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleTLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses.
Publication TypeJournal Article
Year of Publication2013
AuthorsCohen, HB, Briggs, KT, Marino, JP, Ravid, K, Robson, SC, Mosser, DM
JournalBlood
Volume122
Issue11
Pagination1935-45
Date Published2013 Sep 12
ISSN1528-0020
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.

DOI10.1182/blood-2013-04-496216
Alternate JournalBlood
PubMed ID23908469
PubMed Central IDPMC3772500