Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and Gβγ-dependent pathways

Byeong Ho Kang; Young Jun Shim; Yoo Keung Tae; Jin A. Song; Byong Kwan Choi; In Sun Park; Bon Hong Min

doi:10.1016/j.bbrc.2014.02.071

Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and G_βγ-dependent pathways

Byeong Ho Kang, Young Jun Shim, Yoo Keung Tae, Jin A. Song, Byong Kwan Choi, In Sun Park, Bon Hong Min

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the G_αi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a G_βγ inhibitor), indicating the involvement of G_βγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of G_βγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that G_βγ released from the PTX-sensitive G_i protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and G_βγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and G_βγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.

Original language	English
Pages (from-to)	645-650
Number of pages	6
Journal	Biochemical and biophysical research communications
Volume	445
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2014.02.071
Publication status	Published - 2014 Mar 14

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea ( NRF-2012R1A1A2000904 ) and a Korea University grant (K1220371).

Keywords

Chemotaxis
Clusterin
G-protein-coupled receptor
Macrophage
Pertussis toxin

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1016/j.bbrc.2014.02.071

Cite this

Clusterin stimulates the chemotactic migration of macrophages through a pertussis toxin sensitive G-protein-coupled receptor and G_βγ-dependent pathways. / Kang, Byeong Ho; Shim, Young Jun; Tae, Yoo Keung et al.
In: Biochemical and biophysical research communications, Vol. 445, No. 3, 14.03.2014, p. 645-650.

Research output: Contribution to journal › Article › peer-review

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abstract = "Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the Gαi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a Gβγ inhibitor), indicating the involvement of Gβγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of Gβγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that Gβγ released from the PTX-sensitive Gi protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and Gβγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and Gβγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.",

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AU - Song, Jin A.

AU - Choi, Byong Kwan

AU - Park, In Sun

AU - Min, Bon Hong

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