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Macrophage Differentiation Involves Activation of the Unfolded Protein Response
Author(s) -
Dickhout Jeffrey G.,
Colgan Stephen,
Hilditch Brooke,
Basseri Sana,
Lhoták Šárka,
Sood Sudesh K.,
Austin Richard C.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.924.11
Subject(s) - unfolded protein response , macrophage , xbp1 , microbiology and biotechnology , downregulation and upregulation , heat shock protein , endoplasmic reticulum , chemistry , immunology , biology , rna splicing , biochemistry , in vitro , rna , gene
To determine if the unfolded protein response (UPR) is activated during macrophage differentiation and is cytoprotective to macrophages in atherosclerosis, human peripheral blood monocytes were treated with macrophage colony stimulating factor to induce differentiation. Differentiation was assessed as well as UPR activation. UPR markers upregulated during differentiation included the protein folding chaperones GRP78, GRP94 and calnexin and XBP‐1 mRNA splicing. However, the expression of these UPR markers was temporally distinct from ER stress‐induced UPR, did not saturate as further induction occurred with ER stress and did not involve oxidative stress. A dramatic increase in protein synthesis (31‐fold), measured by 35 S‐ methionine incorporation, preceded UPR activation. Cytoprotection against ER stress followed UPR activation or plasmid‐mediated GRP78 overexpression. In early atherosclerotic lesions of apoE −/− mice, GRP78 was markedly increased in resident macrophages, but not monocytes. Our findings demonstrate that UPR activation occurs as a physiological response to increased protein synthesis during macrophage differentiation and is cytoprotective. This may represent an important mechanism for macrophage survival in atherosclerotic lesions, contributing to lesion development and progression. Supported by the Heart and Stroke Foundation of Ontario (T‐5385) and the CIHR (MOP‐74477).