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 4

Epithelial cell death, myofibroblasts, and macrophage cell expansion are all attenuated by rhPTX-2.

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Epithelial cell death, myofibroblasts, and macrophage cell expansion are...
(A) Images of apoptotic tubular epithelial cells (TUNEL+), macrophages (F4/80+), myeloid cells (CD11b+), and myofibroblasts (α-SMA+) in kidney at 9 weeks. Insets show a glomerulus labeled for CD11b expression. (B) Tubular apoptosis, (C) macrophages, (D) myeloid cells, and (E) myofibroblasts. (F) CD11b+ cells per glomerular tuft. (G and H) Q-PCR measuring Acta2 and Col1a1 transcripts in whole kidney tissue. (I) Quantification of peritubular capillary density. Scale bars: 50 μm. n = 6–12/group. *P < 0.05, **P < 0.01 (ANOVA with post hoc testing for multiple comparisons). Avg, average; VEH, vehicle.