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; Yifan Zhan; Jacinta Hansen; Duong Nhu; Guillaume Lessene; Ian P. Wicks; Andrew M. Lew

doi:10.1182/BLOODADVANCES.2020004139

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. SutherlandYifan Zhan, Jacinta Hansen, Duong Nhu, Guillaume Lessene, Ian P. Wicks, Andrew M. Lew

Research output: Contribution to journal › Article › Research › peer-review

12 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2550-2562
Number of pages	13
Journal	Blood Advances
Volume	5
Issue number	11
DOIs	https://doi.org/10.1182/BLOODADVANCES.2020004139
Publication status	Published - 8 Jun 2021

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10.1182/BLOODADVANCES.2020004139

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Carrington, E. M., Louis, C., Kratina, T., Hancock, M., Keenan, C. R., Iannarella, N., Allan, R. S., Wardak, A. Z., Czabotar, P. E., Herold, M. J., Schenk, R. L., White, C. A., D'Silva, D., Yang, Y., Wong, W., Wong, H., Bryant, V. L., Huntington, N. D., Rautela, J., ... Lew, A. M. (2021). BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia. Blood Advances, 5(11), 2550-2562. https://doi.org/10.1182/BLOODADVANCES.2020004139

@article{df8b3395852e4a46b6e55228034c3809,

title = "BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia",

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. ",

author = "Carrington, {Emma M.} and Cynthia Louis and Tobias Kratina and Manuela Hancock and Keenan, {Christine R.} and Nadia Iannarella and Allan, {Rhys S.} and Wardak, {Ahmad Z.} and Czabotar, {Peter E.} and Herold, {Marco J.} and Schenk, {Robyn L.} and White, {Christine A.} and Damian D'Silva and Yuyan Yang and Wesley Wong and Huon Wong and Bryant, {Vanessa L.} and Huntington, {Nicholas D.} and Jai Rautela and Sutherland, {Robyn M.} and Yifan Zhan and Jacinta Hansen and Duong Nhu and Guillaume Lessene and Wicks, {Ian P.} and Lew, {Andrew M.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2021 by The American Society of Hematology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jun,

day = "8",

doi = "10.1182/BLOODADVANCES.2020004139",

language = "English",

volume = "5",

pages = "2550--2562",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

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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 2021, 'BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia', Blood Advances, vol. 5, no. 11, pp. 2550-2562. https://doi.org/10.1182/BLOODADVANCES.2020004139

TY - JOUR

T1 - BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia

AU - Carrington, Emma M.

AU - Louis, Cynthia

AU - Kratina, Tobias

AU - Hancock, Manuela

AU - Keenan, Christine R.

AU - Iannarella, Nadia

AU - Allan, Rhys S.

AU - Wardak, Ahmad Z.

AU - Czabotar, Peter E.

AU - Herold, Marco J.

AU - Schenk, Robyn L.

AU - White, Christine A.

AU - D'Silva, Damian

AU - Yang, Yuyan

AU - Wong, Wesley

AU - Wong, Huon

AU - Bryant, Vanessa L.

AU - Huntington, Nicholas D.

AU - Rautela, Jai

AU - Sutherland, Robyn M.

AU - Zhan, Yifan

AU - Hansen, Jacinta

AU - Nhu, Duong

AU - Lessene, Guillaume

AU - Wicks, Ian P.

AU - Lew, Andrew M.

N1 - Funding Information: 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. Publisher Copyright: © 2021 by The American Society of Hematology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6/8

Y1 - 2021/6/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85108366178&partnerID=8YFLogxK

U2 - 10.1182/BLOODADVANCES.2020004139

DO - 10.1182/BLOODADVANCES.2020004139

M3 - Article

C2 - 34100903

AN - SCOPUS:85108366178

SN - 2473-9529

VL - 5

SP - 2550

EP - 2562

JO - Blood Advances

JF - Blood Advances

IS - 11

ER -

BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia

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The axis of Bcl-2, plasmacytoid DCs and lupus as a basis for therapy

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BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia

Abstract

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The axis of Bcl-2, plasmacytoid DCs and lupus as a basis for therapy

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