PARP-1 controls NK cell recruitment to the site of viral infection
Qiyang Shou, Huiying Fu, Xiaopei Huang, Yiping Yang
Qiyang Shou, Huiying Fu, Xiaopei Huang, Yiping Yang
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Research Article Immunology Virology

PARP-1 controls NK cell recruitment to the site of viral infection

Abstract

The activation and recruitment of NK cells to the site of viral infection are crucial for virus control. However, it remains largely unknown what controls the recruitment of the activated NK cells to the infection site. In a model of intraperitoneal infection with vaccinia virus (VV), we showed that poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, is critical for NK cell recruitment to the site of infection and viral control in vivo. We further demonstrated that PARP-1 promotes the production of CCL2 and that the CCL2-CCR2 axis is essential for NK cell recruitment to the infection site. In addition, we demonstrated that peritoneal macrophages are the main producer of PARP-1–dependent CCL2 secretion. Mechanistically, PARP-1 functions as a regulator of NF-κB by promoting its nuclear translocation and binding to its response sequences in macrophages upon VV infection. Taken together, our results reveal a potentially previously unknown role for PARP-1–dependent CCL2 production in NK cell migration and viral control and may provide important insights into the design of effective NK cell–based therapies for viral infections and cancer.

Authors

Qiyang Shou, Huiying Fu, Xiaopei Huang, Yiping Yang

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Figure 4

CCL2 is responsible for NK cell recruitment to the site of VV infection.

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CCL2 is responsible for NK cell recruitment to the site of VV infection....
(A) C57B/L6 mice were infected with VV (5 × 106 PFU, i.p.) or left uninfected (Naive). 72 hours later, the peritoneal CD3–DX5+ NK cells and the peritoneal fluid were collected for in vitro NK cell migration assay using the Transwell chamber. The peritoneal fluid was mixed with a neutralizing anti-CCL2 antibody (2 μg/ml) or a control Ig and added in the lower chamber, and NK cells were added to the upper chamber. After 5 hours incubation at 37°C, the number of NK cells migrated to the lower chamber was measured. The data represent %NK cells ± SD (n = 4) migrated to the lower chamber over total input NK cells on the upper chamber. (B) C57BL/6 mice were treated with anti-CCL2–neutralizing antibody (20 μg per mouse, daily beginning day –1) or a control Ig. On day 0, mice were infected with VV (5 × 106 PFU, i.p.) or left uninfected (naive). Three days later, peritoneal fluid was harvested and assayed for DX5+CD3– NK cells by flow cytometry. The mean absolute NK cell numbers ± SD are shown (n = 3). **P < 0.01, 2-tailed Student’s t test.