BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia
- Carrington, EM; Louis, C; Kratina, T; Hancock, M; Keenan, CR; Iannarella, N; Allan, RS; Wardak, AZ; Czabotar, PE; Herold, MJ; Schenk, RL; White, CA; D'Silva, D; Yang, Y; Wong, W; Wong, H; Bryant, VL; Huntington, ND; Rautela, J; Sutherland, RM; Zhan, Y; Hansen, J; Nhu, D; Lessene, G; Wicks, IP; Lew, AM;
Publication Year 2021-06-08, Volume 5, Issue #11, Page 2550-2562
- Journal Title
- Blood advances
- Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases.
- WEHI Research Division(s)
- Immunology; Chemical Biology; Blood Cells And Blood Cancer; Inflammation; Structural Biology
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-06-10 11:46:58Last Modified: 2021-06-10 12:06:39