Lung surfactant levels are regulated by Ig-Hepta/GPR116 by monitoring surfactant protein D

Taku Fukuzawa; Junji Ishida; Akira Kato; Taro Ichinose; Donna Maretta Ariestanti; Tomoya Takahashi; Kunitoshi Ito; Jumpei Abe; Tomohiro Suzuki; Shigeharu Wakana; Akiyoshi Fukamizu; Nobuhiro Nakamura; Shigehisa Hirose

doi:10.1371/journal.pone.0069451

Lung surfactant levels are regulated by Ig-Hepta/GPR116 by monitoring surfactant protein D

PLoS One. 2013 Jul 29;8(7):e69451. doi: 10.1371/journal.pone.0069451. Print 2013.

Authors

Taku Fukuzawa¹, Junji Ishida, Akira Kato, Taro Ichinose, Donna Maretta Ariestanti, Tomoya Takahashi, Kunitoshi Ito, Jumpei Abe, Tomohiro Suzuki, Shigeharu Wakana, Akiyoshi Fukamizu, Nobuhiro Nakamura, Shigehisa Hirose

Affiliation

¹ Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.

Abstract

Lung surfactant is a complex mixture of lipids and proteins, which is secreted from the alveolar type II epithelial cell and coats the surface of alveoli as a thin layer. It plays a crucial role in the prevention of alveolar collapse through its ability to reduce surface tension. Under normal conditions, surfactant homeostasis is maintained by balancing its release and the uptake by the type II cell for recycling and the internalization by alveolar macrophages for degradation. Little is known about how the surfactant pool is monitored and regulated. Here we show, by an analysis of gene-targeted mice exhibiting massive accumulation of surfactant, that Ig-Hepta/GPR116, an orphan receptor, is expressed on the type II cell and sensing the amount of surfactant by monitoring one of its protein components, surfactant protein D, and its deletion results in a pulmonary alveolar proteinosis and emphysema-like pathology. By a coexpression experiment with Sp-D and the extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation, we identified Sp-D as the ligand of Ig-Hepta/GPR116. Analyses of surfactant metabolism in Ig-Hepta(+/+) and Ig-Hepta(-/-) mice by using radioactive tracers indicated that the Ig-Hepta/GPR116 signaling system exerts attenuating effects on (i) balanced synthesis of surfactant lipids and proteins and (ii) surfactant secretion, and (iii) a stimulating effect on recycling (uptake) in response to elevated levels of Sp-D in alveolar space.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1,2-Dipalmitoylphosphatidylcholine / metabolism
Animals
Cell Count
Gene Expression Regulation, Developmental
Gene Targeting
Hypertrophy
Immunohistochemistry
In Situ Hybridization
Ligands
Lung / abnormalities
Lung / metabolism*
Lung / pathology
Macrophages, Alveolar / metabolism
Macrophages, Alveolar / pathology
Matrix Metalloproteinase 12 / metabolism
Mice
Mice, Transgenic
Models, Biological
Protein Binding
Protein Biosynthesis
Protein Structure, Tertiary
Pulmonary Surfactant-Associated Protein D / metabolism*
Pulmonary Surfactants / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / deficiency
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
beta-Galactosidase / metabolism

Substances

Gpr116 protein, mouse
Ligands
Pulmonary Surfactant-Associated Protein D
Pulmonary Surfactants
RNA, Messenger
Receptors, G-Protein-Coupled
1,2-Dipalmitoylphosphatidylcholine
beta-Galactosidase
Matrix Metalloproteinase 12

Grants and funding

This work was supported by Grant-in-Aid for Scientific Research on Priority Areas (21026010) and Innovative Areas (24117707), COE21 and GCOE Programs from Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), JSPS Research Fellowships for Young Scientists, and JSPS Grants-in-Aid for Scientific Research (S, 14104002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.