DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes Journal Article
| Authors: | Johnson, D. C.; Okondo, M. C.; Orth, E. L.; Rao, S. D.; Huang, H. C.; Ball, D. P.; Bachovchin, D. A. |
| Article Title: | DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes |
| Abstract: | Canonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4+ and CD8+ T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals. © 2020, The Author(s). |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; nonhuman; sensitivity analysis; cd3 antigen; cd8+ t lymphocyte; animal cell; mouse; animal tissue; bortezomib; etoposide; interleukin 1beta; animal experiment; b lymphocyte; cd4+ t lymphocyte; rat; natural killer cell; glyceraldehyde 3 phosphate dehydrogenase; macrophage; lymphocyte; granulocyte colony stimulating factor; interleukin 1beta converting enzyme; lymphoid cell; bestatin; interleukin 3; pyroptosis; inflammasome; human; male; female; priority journal; article; talabostat; card8 protein; dipeptidyl peptidase; dipeptidyl peptidase 8; dipeptidyl peptidase 9; belnacasan; cd6 antigen; raw 264.7 cell line |
| Journal Title: | Cell Death & Disease |
| Volume: | 11 |
| Issue: | 8 |
| ISSN: | 2041-4889 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-08-14 |
| Start Page: | 628 |
| Language: | English |
| DOI: | 10.1038/s41419-020-02865-4 |
| PUBMED: | 32796818 |
| PROVIDER: | scopus |
| PMCID: | PMC7428001 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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