Repression of Arginase-2 Expression in Dendritic Cells by MicroRNA-155 Is Critical for Promoting T Cell Proliferation

Abstract

Arginine, a semiessential amino acid implicated in diverse cellular processes, is a substrate for two arginases—Arg1 and Arg2—having different expression patterns and functions. Although appropriately regulated Arg1 expression is critical for immune responses, this has not been documented for Arg2. We show that Arg2 is the dominant enzyme in dendritic cells (DCs) and is repressed by microRNA-155 (miR155) during their maturation. miR155 is known to be strongly induced in various mouse and human DC subsets in response to diverse maturation signals, and miR155-deficient DCs exhibit an impaired ability to induce Ag-specific T cell responses. By means of expression profiling studies, we identified Arg2 mRNA as a novel miR155 target in mouse DCs. Abnormally elevated levels of Arg2 expression and activity were observed in activated miR155-deficient DCs. Conversely, overexpression of miR155 inhibited Arg2 expression. Bioinformatic and functional analyses confirmed that Arg2 mRNA is a direct target of miR155. Finally, in vitro and in vivo functional assays using DCs exhibiting deregulated Arg2 expression indicated that Arg2-mediated arginine depletion in the extracellular milieu impairs T cell proliferation. These results indicate that miR155-induced repression of Arg2 expression is critical for the ability of DCs to drive T cell activation by controlling arginine availability in the extracellular environment.

MicroRNAs affect dendritic cell function and phenotype

“…Expression of miR‐155 is induced rapidly in both human and mouse DC following maturation induced by either TLR activation (for example by dsRNA), cytokines [for example IL‐1 β , TNF‐ α and interferon‐ γ (IFN‐ γ )] as well as lipids (such as oxidized low‐density lipoproteins and low‐density lipoproteins) . Expression of miR‐155 by murine DC has been shown to be important for both their maturation and function, as highlighted by the observation that miR‐155‐deficient mice display impaired immune responses to pathogens .…”

“…Expression of miR‐155 by murine DC has been shown to be important for both their maturation and function, as highlighted by the observation that miR‐155‐deficient mice display impaired immune responses to pathogens . This observation being due in part to reduced expression of CD40 and CD86 following TLR activation . The DCs isolated from miR‐155‐deficient mice also have an impaired ability to activate antigen‐specific T cells .…”

“…The DCs isolated from miR‐155‐deficient mice also have an impaired ability to activate antigen‐specific T cells . Recently, the mechanism by which miR‐155 modulates the ability of DC to activate T cells has been described . Dunand‐Sauthier et al .…”

Arginine and NASH – Do macrophages deliver the first hit?

“…In the context of metabolic syndrome and inflammatory diseases, the conversion of arginine to NO and citrulline by NO synthases (NOS) and also its conversion to ornithine and urea by arginases have been of special interest. Interestingly, macrophages and dendritic cells express also the second arginase isoform, arginase 2, a predominantly mitochondrial protein [4,7,8]. Induction of iNOS is a hallmark of classically activated (M1) macrophages and type 1 T helper (Th1) cell responses with iNOS producing oxidative stress, thus promoting antipathogen responses [1,2] but also metabolic disorders, such as insulin resistance [3].…”

“…This finding is remarkable, as arginase 2 is not expressed in hepatocytes but rather in extra-hepatic organs, such as intestine and kidney as well as in macrophages and dendritic cells [4][5][6][7][8]. Depletion of hepatic, but not of adipose tissue macrophages by clodronate at least partially reversed the induction of lipogenic genes and hepatic steatosis that were observed in Arg2 À/À mice.…”