BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia
Emma M Carrington, Cynthia Louis, Tobias Kratina, Manuela Hancock, Christine R Keenan, Nadia Iannarella, Rhys S Allan, Ahmad Z Wardak, Peter E Czabotar, Marco J Herold, Robyn L Schenk, Christine A White, Damian D'Silva, Yuyan Yang, Wesley Wong, Huon Wong, Vanessa L Bryant, Nicholas D Huntington, Jai Rautela, Robyn M Sutherland Show all
BLOOD ADVANCES | AMER SOC HEMATOLOGY | Published : 2021
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..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
Awarded by NHMRC Independent Research Institutes Infrastructure Support Scheme
This work was supported by Arthritis Australia (Grant-in-Aid to E.C. and C.L.), Rebecca L. Cooper Foundation, Reid Charitable Trusts (I.W.), and National Health and Medical Research Council of Australia (NHMRC) grants and fellowships (#1143976, #1150425, #1080321, #1105209 to A.L.; #1113577 to I.W.; and #1125436 to C.K). The NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and the Victorian State Government Operational Infrastructure Support grant is acknowledged.