Matricellular Protein CCN1 Activates a Proinflammatory Genetic Program in Murine Macrophages
Open accessAbstract
CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-α to be cytotoxic without blocking NF-κB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin αMβ2 and syndecan-4, activates NFκB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-α, IL-1α, IL-1β, IL-6, and IL-12b), chemokines (MIP-1α; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rβ) and anti-inflammatory factors (TGF-β1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-κB by CCN1, leading to the synthesis of cytokines including TNF-α and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNF-α, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1β and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.
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CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells, αIIbβ3 in activated platelets, αMβ2 in monocytes and macrophages, and αDβ2 in macrophage foam cells.
“Subsequent studies have shown that CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells [55,56], αIIbβ3 in activated platelets [57], αMβ2 in monocytes and macrophages [58,59], and αDβ2 in macrophage foam cells [60].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [59]
CCN1 reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB.
“Furthermore, CCN1 supports the adhesion of activated monocytes through integrin αMβ2, and reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB [58,59].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [59]
CCN1 supports adhesion of activated monocytes through integrin αMβ2.
“Furthermore, CCN1 supports the adhesion of activated monocytes through integrin αMβ2, and reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB [58,59].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [59]
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- Authors
- Bai, T., Chen, C.-C., & Lau, L. F.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Lau, Lester F
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-03
- Volume
- 184
- Issue
- 6
- Pages
- 3223-3232
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2832719
- OpenAlex
- W1952903895
- Cited by
- 173
- References
- 65
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 11 · 2022: 6 · 2021: 16 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 7 · 2016: 9 · 2015: 16 · 2014: 15 · 2013: 11 · 2012: 6
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (GM078492)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Keywords
- CYR61, matricellular proteins, macrophages, M1 macrophage polarization, NF-κB activation, TNF-α, Mac-1, syndecan-4, macrophage adhesion, Th1 response, pro-inflammatory gene expression, extracellular matrix, inflammation, cytokines, chemokines, TLR4, TGF-β1, inducible nitric oxide synthase, complement C3, oxidative stress
- MeSH terms
- Animals, Cell Adhesion, Cell Line, Cell Line, Transformed, Gene Expression Regulation, Macrophage Activation, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Signal Transduction, Macrophage-1 Antigen, Cytokines, Extracellular Matrix Proteins, NF-kappa B, Macrophages, Peritoneal, Inflammation Mediators, Chemokines, Oligonucleotide Array Sequence Analysis, Cell Line, Tumor, Mice, Syndecan-4, Cysteine-Rich Protein 61
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