BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia
Details
Publication Year 2021-06-08, Volume 5, Issue #11, Page 2550-2562
Journal Title
Blood advances
Abstract
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.
Publisher
ASH
WEHI Research Division(s)
Immunology; Chemical Biology; Blood Cells And Blood Cancer; Inflammation; Structural Biology
PubMed ID
34100903
Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2020004139
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-06-10 11:46:58
Last Modified: 2021-06-10 12:06:39
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