Arginase-1 Expression in Myeloid Cells Regulates Staphylococcus aureus Planktonic but Not Biofilm Infection

Abstract

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 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 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 mice. Despite Arg-1 expression in biofilm-associated myeloid cells, bacterial burdens and leukocyte infiltrates were similar between wild-type (WT) and; 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 ; animals, suggesting a potential Arg-1-independent compensatory mechanism for MDSC-mediated immunomodulation. Treatment of ; 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 burdens were significantly increased in; 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.

Interleukin-10 Produced by Myeloid-Derived Suppressor Cells Provides Protection to Carbapenem-ResistantKlebsiella pneumoniaeSequence Type 258 by Enhancing Its Clearance in the Airways

“…In response to bacterial infection, MDSC recruitment and activity are typically associated with resolution and/or chronicity (28). This has been described during pulmonary infections caused by Pseudomonas aeruginosa (28) and nonpulmonary infections with major pathogens such as Staphylococcus aureus, Salmonella enterica, and Porphyromonas gingivalis (10,13,14,(29)(30)(31)(32)(33)(34). In each of these cases, recruited MDSCs inhibit the innate and adaptive immune responses, causing chronic infection.…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…It is reported that Arg1 secreted by MDSCs can deprive L‐Arginine in the tumor microenvironment, and thereby results in downregulation of TCR‐ζ chain . The increase in the activity of Arg1 in MDSCs causes the decomposition of arginine, and then lead to the decrease of L‐arginine, and finally inhibits the proliferation and functions of T cells by various mechanisms, including the downregulation of the expression of CD3 and the inhibition of cyclin D3 and cyclin‐dependent kinase 4 expression which results in the stagnation of T cell cycle in G0/G1 phase . Besides arginine, in tumor microenvironment, MDSC also inhibits T cell function by expressing IDO.…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…Although IL‐10 production by MDSCs is not required to inhibit T cell proliferation, it is essential for the expansion of MDSCs, for bacterial persistence in orthopedic implants, and for the expression of other cytokines . Arg‐1 expression by MDSCs modulates the infection and the bacterial load within soft tissues around the medical device, where S. aureus remains in planktonic form . Recent data revealed that in a chronic S. aureus infection, Eo‐MDSCs expand and suppress the function of T cells by the expression of iNOS and the subsequent depletion of L‐arginine …”

“…25 Arg-1 expression by MDSCs modulates the infection and the bacterial load within soft tissues around the medical device, where S. aureus remains in planktonic form. 26 Recent data revealed that in a chronic In a murine model, P. aeruginosa also induced the expansion of G-MDSCs to the airways, where they were highly effective in suppressing T cell proliferation. 29 P. gingivalis is the main causative agent of periodontal disease.…”