Harnessing noncoding RNA-based macrophage polarization: Emerging therapeutic opportunities for fibrosis

Abstract

Aim: Organ fibrosis is a common pathological outcome of persistent tissue injury correlated with organ failure and death. Although current antifibrotic therapies have led to unprecedented successes, only a minority of patients with fibrosis benefit from these treatments. There is an urgent need to identify new targets and biomarkers that could be exploited in the diagnosis and treatment of fibrosis.

Methods: Macrophages play a dual role in the fibrogenesis across different organs either by promoting pro-inflammatory or anti-inflammatory responses. Noncoding RNAs (ncRNAs) have been demonstrated to play key roles in macrophage functions by manipulating macrophage polarization. Therefore, understanding the mechanism of ncRNA-associated macrophage polarization is important to move toward therapeutic interventions.

Results: In this review, we provide an overview of recent insights into the role of ncRNAs in different fibrotic diseases by modulating macrophage phenotypic plasticity and functional heterogeneity. We also discuss the potential mechanisms of different ncRNAs integrate heterogeneous macrophages in fibrogenesis,including regulatory signatures, networks, and reciprocal interactions.

Conclusions: A broader understanding of how ncRNA-directed macrophage phenotype transition in immunity and fibrosis might promote the development of a novel strategy for antifibrotic treatment.

Keywords: circular RNA; fibrosis; long noncoding RNA; macrophage polarization; microRNA.

Figure 1

Noncoding genes account for most transcription from the genome. Eukaryotic genomes are extensively transcribed, forming both messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). Of note, ncRNAs remarkably differ from their better‐known counterpart mRNAs, including transcripts numbers and functions. Although these ncRNAs that do not code for proteins, they may affect gene expression and disease progression through a variety of mechanisms

Figure 2

An expanding universe of ncRNA classification and function. Accumulating evidence has uncovered the presence and importance of ncRNAs, which includes miRNAs, lncRNAs, and circRNAs. Intensive research studies have revealed that different ncRNAs play key roles in a great variety of processes, including transcriptional regulation, chromosome replication, RNA processing and modification, mRNA stability and translation, and even protein degradation and translocation. circRNA, circular RNA; lncRNA, long noncoding RNA; mRNA, messenger RNA; miRNA, microRNA; ncRNA, noncoding RNA; RBP, RNA‐binding protein

Figure 3

Crosstalk between heterogeneous macrophages and ncRNAs in liver fibrosis. Liver fibrosis could be induced by different etiologies (CCl4, LPS, schistosomiasis, hepatitis virus, etc). Heterogeneous macrophages (M1 and M2) contribute to the progression and regression of liver fibrosis by regulating the proliferation and activation of HSCs. HF, hepatic fibrosis; HSC, hepatic stellate cell; LPS, lipopolysaccharide; ncRNA, noncoding RNA

Figure 4

Emerging roles for ncRNAs in pulmonary fibrosis by targeting heterogeneous macrophages. Pulmonary fibrosis is now generally regarded as a consequence of multiple risk factors, such as cigarette smoke, irradiation, and silica. ncRNAs have been implicated in the pathogenesis of pulmonary fibrosis, which is associated with the function of heterogeneous macrophages. COPD, chronic obstructive pulmonary disease; lncRNA, long noncoding RNA; LPS, lipopolysaccharide; miR, microRNA; ncRNA, noncoding RNA

Figure 5

Noncoding RNA‐mediated macrophage phenotypic regulation in renal fibrosis. Renal fibrosis contributes greatly to end‐stage renal failure, characterized by the excessive ECM deposition in the interstitium of kidney. In response to the different injuries, infiltrating and resident macrophages could undergo M1 or M2 polarization, which is largely dependent on the regulation of multiple noncoding RNAs. ECM, extracellular matrix; IR, ischemia‐reperfusion; RF, renal fibrosis

Figure 6

Noncoding RNA‐associated macrophage polarization regulatory networks in cardiac fibrosis. Cardiac fibrosis (CF) is considered as an important and early risk factor for cardiac development and diseases, triggered by variable etiology. Noncoding RNAs play an important role in the pathogenesis of CF by targeting M1 or M2 polarization