Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease
Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield
Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield
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Research Article Immunology Inflammation

Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease

Abstract

Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level is decreased in chronic human fibrotic diseases. Here we show that recombinant human PTX-2 (rhPTX-2) retards progression of chronic kidney disease in Col4a3 mutant mice with Alport syndrome, reducing blood markers of kidney failure, enhancing lifespan by 20%, and improving histological signs of disease. Exogenously delivered rhPTX-2 was detected in macrophages but also in tubular epithelial cells, where it counteracted macrophage activation and was cytoprotective for the epithelium. Computational analysis of genes regulated by rhPTX-2 identified the transcriptional regulator c-Jun along with its activator protein–1 (AP-1) binding partners as a central target for the function of rhPTX-2. Accordingly, PTX-2 attenuates c-Jun and AP-1 activity, and reduces expression of AP-1–dependent inflammatory genes in both monocytes and epithelium. Our studies therefore identify rhPTX-2 as a potential therapy for chronic fibrotic disease of the kidney and an important inhibitor of pathological c-Jun signaling in this setting.

Authors

Naoki Nakagawa, Luke Barron, Ivan G. Gomez, Bryce G. Johnson, Allie M. Roach, Sei Kameoka, Richard M. Jack, Mark L. Lupher Jr., Sina A. Gharib, Jeremy S. Duffield

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Figure 6

Gene set enrichment analysis identifies attenuated c-Jun signaling as a direct and central consequence of PTX-2 treatment.

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Gene set enrichment analysis identifies attenuated c-Jun signaling as a ...
(A) Principal component analysis of kidney transcriptome. Treatment of Col4a3–/– mice with rhPTX-2 partly reverses separation from the uninjured Col4a3+/+ animals, indicating rhPTX-2 therapy reduced transcriptional perturbation. (B) Summary of pathway analysis (GSEA) depicted as heatmaps of individual leading-edge genes (rows) and individual mice (columns). Enriched gene sets fell into 4 broad functional categories induced by disease: mitochondrion/oxidoreductase activity, metabolism, inflammation/immunity, and tissue remodeling. Within each category, PTX-2 treatment of Col4a3–/– mice partly restored disease-induced gene expression changes to their unperturbed baseline. Note only AP-1 signaling (blue box) was suppressed below baseline levels by rhPTX-2. (C) Abbreviated protein-protein interaction network predicted by STRING analysis of the top 100 leading-edge genes identified by GSEA and downregulated by rhPTX-2 treatment. Line color denotes type of evidence: green: neighborhood, red: gene fusion, blue: co-occurrence, black: coexpression, purple: experiments, cyan: databases, yellow: text mining, and lilac: homology. (D) Western blots showing the effect of disease and PTX-2 treatment on p–S63-c-Jun, total c-Jun, and C/EBP in kidney tissue. VEH, vehicle.