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 7

rhPTX-2 directly attenuates c-Jun and AP-1 complex signaling in human monocytes.

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rhPTX-2 directly attenuates c-Jun and AP-1 complex signaling in human mo...
(A and B) Time-course Western blots (A) and densitometry quantification (B) showing c-Jun phosphorylation (p–S63-c-Jun) and total c-Jun levels from 15 to 60 minutes after rhPTX-2 and/or TNF-α stimulation in human iPSC-derived monocytes, normalized to GAPDH. Note that rhPTX-2 attenuates both total and p–c-Jun in response to TNF-α. Data represent 3 experiments. (C) Effect of concentrations of PTX-2 or AP-1 inhibitor SR11302 on TNF-α–induced AP1/NF-κB promoter activity in human monocytes. (D) Effect of concentrations of PTX-2 on TNF-α–induced AP-1 promoter activity alone, in human monocytes. (E) rhPTX-2–induced changes in the secretion of factors associated with fibrosis by primary human monocytes cultured from 12 to 120 hours. Presence of c-Jun and AP-1 binding sites in the promoters of these genes is indicated, based on the GeneCards database. n = 3–8/group (*P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA with post hoc testing for multiple comparisons). VEH, vehicle; AlkPhos, alkaline phosphatase.