Journal article
CD52 inhibits Toll-like receptor activation of NF-κB and triggers apoptosis to suppress inflammation
M Rashidi, E Bandala-Sanchez, KE Lawlor, Y Zhang, AM Neale, SL Vijayaraj, R O'Donoghue, JM Wentworth, TE Adams, JE Vince, LC Harrison
Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2018
DOI: 10.1038/cdd.2017.173
Abstract
Soluble CD52 is a small glycoprotein that suppresses T-cell activation, but its effect on innate immune cell function is unknown. Here we demonstrate that soluble CD52 inhibits Toll-like receptor and tumor necrosis factor receptor signaling to limit activation of NF-κB and thereby suppress the production of inflammatory cytokines by macrophages, monocytes and dendritic cells. At higher concentrations, soluble CD52 depletes the short-lived pro-survival protein MCL-1, contributing to activation of the BH3-only proteins BAX and BAK to cause intrinsic apoptotic cell death. In vivo, administration of soluble CD52 suppresses lipopolysaccharide (LPS)-induced cytokine secretion and other features of..
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Awarded by State Government of Victoria
Funding Acknowledgements
We thank G. Naselli, K. Ngui, J. Bosco, N. Stone, R. Boehmer, N. Khan, L. Dagley, P. Nguyen for technical assistance and advice. We thank I. Wicks, J. Murphy, H. Thomas, S.L. Masters, A. Webb, R. Feltham, E. Petrie, S. Nicholson for insightful discussions. We thank L. Schofield for providing THP-1 cells, N. Lalaoui, D. Vaux and J. Silke for the ERK inhibitors and PARP antibody, NF-kappa B reporter, GEV-16 and MCL-1 cDNA constructs. G. Salvesen and M. Navarro for the inducible cFLIPL cDNA construct, P. Meier for the IKK-EE mutant construct and D. Huang, K. Mason and D. Gray for BAX/BAK double knockout mice, O. Takeuchi for the Bax<SUP>fl/fl</SUP> Bak<SUP>-/-</SUP> strain and J. Gilbert, M. Dayton, D. Cooper for technical assistance. This work was supported by the National Health and Medical Research Council of Australia Program Grant (LCH 1037321), Project Grants (LCH 1051484; JEV 1051210 and 1101405), Fellowships (LCH 1080887; JEV 1052598), and by operational infrastructure grants through the Australian Government IRISS (9000220) and the Victorian State Government OIS.