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Histone functions as a cell-surface receptor for AGEs

ABSTRACT: Reducing sugars can covalently react with proteins to generate a heterogeneous and complex group of compounds called advanced glycation end products (AGEs). AGEs are generally considered as pathogenic molecules, mediating a pro-inflammatory response and contributing to the development of a number of human diseases. However, the intrinsic function of AGEs remains to be elucidated. We now provide multiple lines of evidence showing that AGEs can specifically bind a cell-surface protein and regulate its functions. To identify cellular binding partners for AGEs, we used dehydroascorbic acid (DHA)-modified serum albumins as one of the AGEs to screen for binding proteins in the lipid raft fraction prepared from mouse splenocytes and identified histone localized on the cell-surface as an AGE-binding protein. Histone ubiquitously recognized AGEs, including proteins modified with glucose and its metabolites. AGEs inhibited the binding of plasminogen to the histone component H2B which functions as a cell-surface plasminogen receptor on monocytes/macrophages. Moreover, AGEs regulated the recruitment of monocytes/macrophage to the site of inflammation. Our discovery of histone as a cell-surface receptor for AGEs suggests that, beside our common concept of AGEs as danger-associated molecular patterns mediating a pro-inflammatory response, they may also be involved in the homeostatic response via binding to histone.

ORGANISM(S): Mus musculus

PROVIDER: GSE195558 | GEO | 2022/03/31

REPOSITORIES: GEO

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Project description:Background and Aims Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire ‘gain-of-function’ isoDGR motifs that might play a role in atherosclerotic pathology. Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo. Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor ‘outside in’ signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNF to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin 1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68+ macrophages in vivo. Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of ‘outside-in’ signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.

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Histone functions as a cell-surface receptor for AGEs

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