期刊
INFECTION AND IMMUNITY
卷 86, 期 7, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00206-18
关键词
arginase-1; biofilm; S. aureus; macrophage; myeloid-derived suppressor cell
资金
- NIH National Institute of Allergy and Infectious Diseases (NIAID) [2P01AI083211]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI083211] Funding Source: NIH RePORTER
Staphylococcus aureus is a leading cause of device-associated biofilm infections, which represent a serious health care concern based on their chronicity and antibiotic resistance. We previously reported that S. aureus biofilms preferentially recruit myeloid-derived suppressor cells (MDSCs), which promote monocyte and macrophage anti-inflammatory properties. This is associated with increased myeloid arginase-1 (Arg-1) expression, which has been linked to anti-inflammatory and profibrotic activities that are observed during S. aureus biofilm infections. To determine whether MDSCs and macrophages utilize Arg-1 to promote biofilm infection, Arg-1 was deleted in myeloid cells by use of Tie-2(Cre) mice. Despite Arg-1 expression in biofilm-associated myeloid cells, bacterial burdens and leukocyte infiltrates were similar between wild-type (WT) and Arg-1(fl/fl); Tie-2(Cre) conditional knockout (KO) mice from days 3 to 14 postinfection in both orthopedic implant and catheter-associated biofilm models. However, inducible nitric oxide synthase (iNOS) expression was dramatically elevated in biofilm-associated MDSCs from Arg-1(fl/fl); Tie-2 Cre animals, suggesting a potential Arg-1-independent compensatory mechanism for MDSCmediated immunomodulation. Treatment of Arg-1(fl/fl); Tie-2(Cre) mice with the iNOS inhibitor N6-(1-iminoethyl)-L-lysine (L-NIL) had no effect on biofilm burdens or immune infiltrates, whereas treatment of WT mice with the Arg-1/ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) increased bacterial titers, but only in the surrounding soft tissues, which possess attributes of a planktonic environment. A role for myeloid-derived Arg-1 in regulating planktonic infection was confirmed using a subcutaneous abscess model, in which S. aureus burdens were significantly increased in Arg-1(fl/fl); Tie-2(Cre) mice compared to those in WT mice. Collectively, these results indicate that the effects of myeloid Arg-1 are context dependent and are manifest during planktonic but not biofilm infection.
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