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Mol Immunol. 2017 Dec;92:190-198. doi: 10.1016/j.molimm.2017.10.016. Epub 2017 Nov 4.

Surfactant protein D regulates caspase-8-mediated cascade of the intrinsic pathway of apoptosis while promoting bleb formation.

Author information

1
Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.
2
Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada.
3
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada; Center for Molecular Design and Preformulations, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.
4
Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Departments of Paediatrics, Physiology and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5G 1X8, Canada.
5
Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Departments of Laboratory Medicine and Pathobiology and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. Electronic address: nades.palaniyar@sickkids.ca.

Abstract

Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D on the intrinsic pathway of apoptosis are not clearly understood. In the intrinsic pathway, cytochrome c is released by mitochondria into the cytoplasm. Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade. Both caspase-8- and caspase-9-mediated branches are activated in the intrinsic pathway of apoptosis; however, little is known about the relevance of the caspase-8 pathway in this context. Here we studied the effects of SP-D on different branches of the intrinsic pathway of apoptosis using UV-irradiated Jurkat T-cells. We found that SP-D does not inhibit the caspase-9 branch of apoptosis and the relevance of the caspase-8-related branch became apparent when the caspase-9 pathway was inhibited by blocking cytochrome c oxidase. Under these conditions, SP-D reduces the activation of caspase-8, executioner caspase-3 and exposure of phosphatidylserine (PS) on the membranes of dying cells. By contrast, SP-D increases the formation of nuclear and membrane blebs. Inhibition of caspase-8 confirms the effect of SP-D is unique to the caspase-8 pathway. Overall, SP-D suppresses certain aspects of the intrinsic pathway of apoptosis via reduction of caspase-8 activation and PS flipping while at the same time increasing membrane and nuclear bleb formation. This novel regulatory aspect of SP-D could help to regulate intrinsic pathway of apoptosis to promote effective blebbing and breakdown of dying cells.

KEYWORDS:

Collectins; Intrinsic pathway of apoptosis; Mucosal surface; Surfactant protein D

PMID:
29107869
DOI:
10.1016/j.molimm.2017.10.016
[Indexed for MEDLINE]

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