MicroRNAs and the resolution phase of in?ammation in macrophages

Abstract

Toll-like receptors (TLRs) signal the presence of pathogens and tissue injury, triggering the inflammatory process in macrophages. The goal of inflammation is to resolve the injury and return the body to homeostasis. MicroRNAs are an important group of regulators of TLR signaling and several are induced by TLRs in macrophages. These TLR-induced microRNAs target signaling components in the TLR pathway, thereby producing a negative feedback loop, and they are therefore prime candidates for the initiation of repair. Importantly, their dysregualtion may be important for chronic inflammation, which in turn can lead to autoimmunity and cancer, as discussed in this Viewpoint.

The first line of defense against pathogens is composed primarily of innate immune cells ? specifically phagocytes (macrophages and polymorphonuclear neutrophils). Once the inflammatory response is initiated, the system is brought back to homeostasis by negative regulators. Since there is now ample evidence to indicate that dysregulation of innate immunity can give rise to a range of inflammatory diseases, elaborate control mechanisms must exist to prevent its overactivation. These control mechanisms are likely to be triggered after the initial activation of innate immune receptors (such as the TLRs), their job being to restore the system to homeostasis. In the case of TLR activation, a large number of such controls have been identified, ranging from decoy receptors to phosphatases to deubiquinating enzymes 1. Recently, microRNAs (miRNAs) have emerged as key regulators of TLRs, particularly in macrophages, and it is highly likely that they fine-tune signaling in order to allow for resolution of the inflammatory process.

miRNAs are typically small (21?22 nucleotides) noncoding RNAs, the majority of which are intergenic or intronic, although a minority of miRNAs are derived from protein-coding mRNAs 2. miRNAs form a complex with the RNA-induced silencing complex (RISC) producing miRISCs that bind to complementary 3? UTRs of target genes and thereby repress translation of mRNA, promote degradation, or stabilize the target mRNA 2. Depending on the pathogen encountered, TLRs induce a number of miRNAs with expression of some miRNAs being decreased in response to TLRs 2.

Here, we discuss how miRNAs regulate TLRs, particularly in macrophages, a process likely to occur in the resolution phase of inflammation and speculate on the importance of miRNAs in diseases, which feature dysregulated innate immunity. We discuss three particular miRNAs ? miR-155, miR-146a, and miR-21 ? since these miRNAs have been strongly implicated in the regulation of TLRs in a number of cells including macrophages 3. Interestingly, miR-155 and miR-146 are specifically present in LPS-induced macrophages, as compared with similarly activated polymorphonuclear neutrophils (PMNs), suggesting a particular role for these miRNAs in macrophages 4. We also speculate on the potential novel therapies that target miRNAs in infection and inflammation that could be developed.