Pentraxin-2 suppresses c-Jun/AP-1 signaling to inhibit progressive fibrotic disease
Naoki Nakagawa, … , Sina A. Gharib, Jeremy S. Duffield
Naoki Nakagawa, … , Sina A. Gharib, Jeremy S. Duffield
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e87446. https://doi.org/10.1172/jci.insight.87446.
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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 1

rhPTX-2 localizes to interstitial macrophages and proximal epithelial cells and protects Col4a3–/– mice from kidney disease progression.

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rhPTX-2 localizes to interstitial macrophages and proximal epithelial ce...
Experimental schema indicating rhPTX-2 delivery from 3.5 weeks after birth and (A) analysis at 42 days (6 weeks) and 63 days (9 weeks) or (B) continued to 94 days (14 weeks). (C) Split-panel confocal images of 9-week-old Col4a3–/– kidney cortex showing distribution of rhPTX-2 colocalized with proximal tubular epithelial cells (lotus lectin [LTL], arrows) and macrophages (F4/80, arrowheads). Scale bars: 50 μm. Proportions of (D) hPTX-2+LTL+ proximal tubular epithelial cells and (E) hPTX2+F4/80+ macrophages at 9 weeks after twice weekly i.p. injections of rhPTX-2. (F) Plasma BUN levels at 9 weeks. (G) Urine albumin concentration normalized to urine creatinine at 9 weeks. (H) Body weights from start of treatment to death. (I) Kaplan-Meier survival curve. n = 6–12/group. *P < 0.05, ***P < 0.001 (ANOVA with post hoc testing for multiple comparisons and Gehan-Breslow-Wilcoxon test for survival). VEH, vehicle; n.d., not detected.