Anti-Inflammatory MicroRNAs and Their Potential for Inflammatory Diseases Treatment

Abstract

Inflammation is a complicated biological and pathophysiological cascade of responses to infections and injuries, and inflammatory mechanisms are closely related to many diseases. The magnitude, the complicated network of pro- and anti-inflammatory factors, and the direction of the inflammatory response can impact on the development and progression of various disorders. The currently available treatment strategies often target the symptoms and not the causes of inflammatory disease and may often be ineffective. Since the onset and termination of inflammation are crucial to prevent tissue damage, a range of mechanisms has evolved in nature to regulate the process including negative and positive feedback loops. In this regard, microRNAs (miRNAs) have emerged as key gene regulators to control inflammation, and it is speculated that they are fine-tune signaling regulators to allow for proper resolution and prevent uncontrolled progress of inflammatory reactions. In this review, we discuss recent findings related to significant roles of miRNAs in immune regulation, especially the potential utility of these molecules as novel anti-inflammatory agents to treat inflammatory diseases. Furthermore, we discuss the possibilities of using miRNAs as drugs in the form of miRNA mimics or miRNA antagonists.

Keywords: anti-inflammatory microRNA; immune regulation; inflammation; inflammatory diseases; microRNA.

Figure 1

The biogenesis and function of microRNAs (miRNAs). miRNA is a short non-coding ribonucleic acid originated inter- or intragenicaly by RNA pol III and II, respectively. After initial processing by RNase Drosha in the nucleus, the pre-miRNA is transported to the cytoplasm where the miRNA hairpin is cleaved by endoribonuclease Dicer, forming an miRNA duplex. One of the miRNA strands loads into the RNA inducing silencing complex (RISC) that regulates mRNA transcription and protein translation through various ways. The miRNA binding to its target usually results in mRNA degradation, decreased mRNA stability, or translational inhibition, and hence they can influence transcriptional regulation of target genes. Alternatively miRNAs occasionally can enhance RNA stability and even upregulate transcription and translation of their certain targets. Some evidence also indicated that miRNAs can target long-non-coding RNAs (lncRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs), and regulate expression of other miRNAs.

Figure 2

The broad function of microRNAs (miRNAs) in immune regulation. miRNAs are expressed in immune cells and function as “fine-tuners” for innate and adaptive immune responses. They establish an integrated part of the regulatory networks in innate immunity and regulate functions of immune cells such as monocytes, dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, megakaryocytes, and granulocytes. In adaptive immunity, they are implicated in every biological process including pathways involved in the T and B cells development, differentiation, central and peripheral tolerance, as well as their function.

Figure 3

The spectrum of microRNA (miRNA) effects during inflammation. Inflammation is a complex biological and pathophysiological response in vascular tissues to noxious stimuli, such as infection and tissue damage. The initiation, spread, and resolution steps of inflammation are subject to both positive and negative regulatory events via miRNAs to achieve an optimal immune response (green arrow). The positive feedback is activated to initiate a cascade of molecular events that leads to combat invading microbial pathogens and successful repair of tissue damage. The negative feedback is only activated during severe inflammation and may be vital in preventing potentially dangerous and excessive inflammation. Lack of appropriate initiation or spread impedes the innate immune response, and lack of correct resolution can lead to uncontrolled condition and disease (red arrow). Thus, the molecular networks based on miRNAs that regulate the initiation, spread, and resolution of inflammation must be appropriately tuned for optimization of the innate immune response.

Figure 4

The way anti-inflammatory microRNAs (miRNAs) exert their action to control inflammatory response. miRNAs serve in important negative feedback loops in inflammation processes and inflammatory diseases. By targeting signal transduction proteins involved in the initiation of innate immune response, and by directly targeting mRNAs that encode specific inflammatory mediators, miRNAs can have an important impact on the magnitude of the ensuing inflammatory response.