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THE IDENTIFICATION AND CHARACTERIZATION OF AN INTRINSIC CD39/A2R-BASED REGULATORY MECHANISM THAT GOVERNS MACROPHAGE ACTIVATION RESPONSES

dc.contributor.advisorMosser, David Men_US
dc.contributor.authorCohen, Heather Bloomen_US
dc.date.accessioned2014-06-24T05:39:55Z
dc.date.available2014-06-24T05:39:55Z
dc.date.issued2014en_US
dc.identifier.urihttp://hdl.handle.net/1903/15159
dc.description.abstractMacrophages are acutely sensitive to changes within their environment and can readily develop into a variety of activation states important for both the progression and resolution of inflammation. In response to immunological threats, macrophages must be able to effectively clear infections without sacrificing the integrity of the affected tissue. Thus, these cells must successfully balance their activation responses in order to preserve tissue function and the overall health of the host. The failure to properly regulate macrophage activation responses often manifests in the clinic in a variety of disease scenarios including sepsis, chronic inflammatory disorders, and cutaneous Leishmaniasis. While many factors that drive the initiation of macrophage activation are known, it remains unclear what governs the transition to an immunosuppressive state. This study reveals that macrophages can control their own activation status through the coordination between the ecto-ATPase, CD39, and the adenosine 2a and 2b receptors (A2Rs). The first part of this work shows that soon after toll-like receptor (TLR) stimulation, macrophages secrete and convert ATP into immunosuppressive adenosine via CD39. Moreover, we show that CD39 on macrophages is necessary to induce regulatory macrophage development and prevent severe immunopathology in a mouse model of septic shock. The next sets of data demonstrate that TLR activation also enhances A2bR expression, thus completing the CD39-initiated autoregulatory circuit to limit inflammatory macrophage responses. The second part of this work demonstrates that the chronic inflammatory disease-asociated cytokine, IFN-gamma, prevents TLR-induced A2bR expression and consequently promotes the hyper-production of inflammatory cytokines by macrophages thereby revealing a novel mechanism by which IFN-gamma; maintains overactive macrophages. The final chapter illustrates that while the A2bR is the dominant adenosine receptor mediating the inhibition of inflammatory cytokine production, A2aR signaling inhibits nitric oxide generation and that its expression may be hijacked by intracellular parasites to evade innate host defense mechanisms. Thus, this study demonstrates that inflammatory macrophage activation is inherently transient and that macrophages can reprogram themselves. These results culminate in the discovery of a novel immunomodulatory mechanism reliant on macrophage purinergic signaling and offer new targets and strategies to more effectively treat myriad inflammatory and infectious diseases.en_US
dc.language.isoenen_US
dc.titleTHE IDENTIFICATION AND CHARACTERIZATION OF AN INTRINSIC CD39/A2R-BASED REGULATORY MECHANISM THAT GOVERNS MACROPHAGE ACTIVATION RESPONSESen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.subject.pqcontrolledImmunologyen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pqcontrolledMolecular biologyen_US
dc.subject.pquncontrolledadenosineen_US
dc.subject.pquncontrolledATPen_US
dc.subject.pquncontrolledCD39en_US
dc.subject.pquncontrolledimmunosuppressionen_US
dc.subject.pquncontrolledinflammationen_US
dc.subject.pquncontrolledmacrophageen_US


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