| First Author | Koehn BH | Year | 2019 |
| Journal | Blood | Volume | 134 |
| Issue | 19 | Pages | 1670-1682 |
| PubMed ID | 31533918 | Mgi Jnum | J:282729 |
| Mgi Id | MGI:6379104 | Doi | 10.1182/blood.2019001950 |
| Citation | Koehn BH, et al. (2019) Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD. Blood 134(19):1670-1682 |
| abstractText | Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1beta (IL-1beta), we expected that IL-1beta KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1beta release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1beta added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1beta could diminish survival in GVHD. However, loss of inflammasome activation and IL-1beta release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1beta signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments. |
