Abstract
Inflammation is a natural defence mechanism of the body to protect against pathogens. It is induced by immune cells, such as macrophages and neutrophils, which are rapidly recruited to the site of infection, mediating host defence. The processes for eliminating inflammatory cells after pathogen clearance are critical in preventing sustained inflammation, which can instigate diverse pathologies. During chronic inflammation, the excessive and uncontrollable activity of the immune system can cause extensive tissue damage. New therapies aimed at preventing this over-activity of the immune system could have major clinical benefits. Here, we investigated the role of the pro-survival Bcl-2 family member A1 in the survival of inflammatory cells under normal and inflammatory conditions using murine models of lung and peritoneal inflammation. Despite the robust upregulation of A1 protein levels in wild-type cells upon induction of inflammation, the survival of inflammatory cells was not impacted in A1-deficient mice compared to wild-type controls. These findings indicate that A1 does not play a major role in immune cell homoeostasis during inflammation and therefore does not constitute an attractive therapeutic target for such morbidities.
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Acknowledgements
We acknowledge the invaluable contributions of the animal caretaker staff for animal husbandry and the flow cytometry facility of WEHI.
Funding
This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) (Project Grants 1186575, 1159658 and 1145728 to MJH, 1143105 to MJH and AS), Programme Grant 1016701 to AS and Fellowships 1020363 to AS, 1156095 to MJH, the Leukaemia and Lymphoma Society of America (LLS SCOR 7015-18 to AS and MJH), the Cancer Council of Victoria (project grant 1147328 to MJH, 1052309 to AS and Venture Grant to MJH and AS), the Australian Phenomics Network (to MJH), the Leukaemia and Lymphoma Society Grant #7001-13 to AS; the estate of Anthony (Toni) Redstone OAM and The Craig Perkins Cancer Research Foundation; and operational infrastructure grants through the Australian Government NHMRCS IRIISS and the Victorian State Government Operational Infrastructure Support to AS and the CASS Foundation Science and Medicine Grant #9393 to LG. KF is the recipient of the Alex Gadomski Fellowship, funded by Maddie Riewoldt’s Vision. KDS is supported by the Peter and Julie Alston Centenary Fellowship.
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LG performed and designed most experiments and wrote the manuscript; RLS, SAB, CN, CL, DD, and KF helped to perform experiments and write the manuscript; AJ, HP, and KDS helped with discussions and advice on neutrophil experiments and write the manuscript; AS and MJH planned the project, were involved in experimental design and helped write the manuscript.
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All animal experiments were approved by the Walter and Eliza Hall Institute of Medical Research (WEHI) and the La Trobe University (LTU) Animal Ethics Committees.
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Gangoda, L., Schenk, R.L., Best, S.A. et al. Absence of pro-survival A1 has no impact on inflammatory cell survival in vivo during acute lung inflammation and peritonitis. Cell Death Differ 29, 96–104 (2022). https://doi.org/10.1038/s41418-021-00839-3
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DOI: https://doi.org/10.1038/s41418-021-00839-3
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