CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

Figures

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  Figure 1. Schematic diagram of genes, mRNAs, and proteins of mouse C/EBP family members. The gene location, exons and introns, mRNA information, and protein isoforms of C/EBPs are shown (accessed September 9, 2022, National Center for Biotechnology Information).

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  Figure 2. Posttranslational modifications of C/EBP family members. Two isoforms of C/EBPα, three isoforms of C/EBPβ, and C/EBPγ, C/EBPδ, C/EBPε, and C/EBPζ are shown. The PTMs of C/EBPs mainly include phosphorylation, acetylation, ubiquitination, methylation, and SUMOylation. H in brackets is the abbreviation of human. K193-C/EBPα and T217-C/EBPβ are important sites in fibrosis (DBD: DNA-binding domain; RD: regulatory domain; TAD: transcriptional activation domain; ZIP: leucine zipper).

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  Figure 3. The mechanisms of C/EBPs in liver fibrosis. Hepatic stellate cells (HSCs), portal fibroblasts, hepatocytes, and immune cells such as Kupffer cells and neutrophils play vital roles in hepatic fibrosis. C/EBPs in these cells participate in the fibrotic process of the liver. C/EBPα in HSCs, hepatocytes, and neutrophils all exhibits antifibrotic effects on liver, but p-C/EBPα-S193 can promote hepatic fibrosis in aged liver through different mechanisms. C/EBPβ and C/EBPζ in different cells have different roles in hepatic fibrosis under various stimuli. C/EBPδ of HSCs and hepatocytes can inhibit liver fibrosis.

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  Figure 4. The mechanisms of C/EBPs in lung fibrosis. C/EBPα proteins in both lung fibroblasts and alveolar epithelial cells all exert inhibitory effects on lung fibrosis. C/EBPβ in different cells have different roles in pulmonary fibrosis under various stimuli. C/EBPγ of alveolar epithelial cells can inhibit lung fibrosis. C/EBPδ in lung macrophages and alveolar epithelial cells possess promotive effects on pulmonary fibrosis whereas Clara cell C/EBPδ inhibits lung fibrosis. In addition to its diverse roles in macrophages, C/EBPζ in other cells can promote pulmonary fibrosis under various stimuli.

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  Figure 5. The mechanisms of C/EBPs in kidney fibrosis. C/EBPα proteins in podocytes and collecting duct epithelial cells (CDECs) can inhibit renal fibrosis through various mechanisms whereas it in fibroblasts promotes kidney fibrosis indirectly. C/EBPβ in tubular epithelial cells (TECs) exerts antifibrotic effects while renal macrophage C/EBPβ possesses profibrotic effects on kidney. C/EBPδ proteins in both TECs and mesangial cells exhibit profibrotic effects on kidney. In renal tissues, C/EBPζ upregulation induced by ER stress can promote fibrogenesis.

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  Figure 6. The mechanisms of C/EBPs in heart fibrosis. Among C/EBPs, C/EBPβ, C/EBPδ, and C/EBPζ participate in heart fibrosis. C/EBPβ in cardiac fibroblasts and cardiomyocytes can promote or inhibit cardiac fibrosis depending on different stimuli. C/EBPδ of cardiomyocytes exerts antifibrotic effects on heart fibrosis, while C/EBPζ in various cells possesses different roles in cardiac fibrosis.

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  Figure 7. The mechanisms of C/EBPs in neural fibrosis. Among C/EBPs, C/EBPδ is involved in neural fibrosis. C/EBPδ in microglia can promote neural fibrosis whereas it in pericytes inhibits fibrosis of the nervous system. C/EBPδ of activated astrocytes exerts the profibrotic or antifibrotic effects on neural fibrosis depending on various stimuli.

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  Figure 8. The relationships and mechanisms of C/EBPs in fibrosis of other tissues. The roles of C/EBPs in fibrosis of skeletal muscle, fat, and skin are shown. Under the stimuli, C/EBPα is negatively correlated with skeletal muscle fibrosis and fat fibrosis. Upregulated C/EBPβ can promote the differentiation of adipocytes leading to fibrosis and inhibit the ECM production in dermal fibroblasts to suppress skin fibrosis. C/EBPγ and C/EBPδ can promote skin fibrosis and skeletal muscle fibrosis through various mechanisms, respectively.