The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis
- Moujalled, D; Gangatirkar, P; Kauppi, M; Corbin, J; Lebois, M; Murphy, JM; Lalaoui, N; Hildebrand, JM; Silke, J; Alexander, WS; Josefsson, EC;
Publication Year 2021-01-28, Volume 12, Issue #1, Page 133
- Journal Title
- Cell Death & Disease
- Necroptosis is a pro-inflammatory cell death program executed by the terminal effector, mixed lineage kinase domain-like (MLKL). Previous studies suggested a role for the necroptotic machinery in platelets, where loss of MLKL or its upstream regulator, RIPK3 kinase, impacted thrombosis and haemostasis. However, it remains unknown whether necroptosis operates within megakaryocytes, the progenitors of platelets, and whether necroptotic cell death might contribute to or diminish platelet production. Here, we demonstrate that megakaryocytes possess a functional necroptosis signalling cascade. Necroptosis activation leads to phosphorylation of MLKL, loss of viability and cell swelling. Analyses at steady state and post antibody-mediated thrombocytopenia revealed that platelet production was normal in the absence of MLKL, however, platelet activation and haemostasis were impaired with prolonged tail re-bleeding times. We conclude that MLKL plays a role in regulating platelet function and haemostasis and that necroptosis signalling in megakaryocytes is dispensable for platelet production.
- WEHI Research Division(s)
- Blood Cells And Blood Cancer; Inflammation; Advanced Technology And Biology
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-03-09 01:36:54Last Modified: 2021-03-09 02:31:34