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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • Caspase 3 / immunology
  • Caspase 8 / immunology*
  • Caspase 9 / immunology
  • Cell Membrane Structures / immunology*
  • Cytochromes c / immunology
  • Humans
  • Jurkat Cells
  • Nuclear Envelope / immunology*
  • Pulmonary Surfactant-Associated Protein D / immunology*
  • Signal Transduction / immunology*

Substances

  • Pulmonary Surfactant-Associated Protein D
  • Cytochromes c
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9