MicroRNAs in mucosal inflammation

Abstract

Of the total human body's surface, the majority is internal surface, belonging to the lungs (100 m²) and intestinal tract (400 m²). In comparison, the external surface area, belonging to the skin, comprises less than 1% (2 m²). Continuous exposure of the mucosal surface to external factors (e.g., pathogens, food particles) requires tight regulation to maintain homeostasis. MicroRNAs (miRNAs) have gained noticeable attention as playing important roles in maintaining the steady-state of tissues by modulating immune functions and inflammatory responses. Accordingly, associations have been found between miRNA expression levels and human health conditions and diseases. These findings have important implications in inflammatory diseases involving pulmonary and intestinal mucosa, such as acute lung injury or inflammatory bowel disease. In this review, we highlight the known biology of miRNAs and discuss the role of miRNAs in modulating mucosal defense and homeostasis. Additionally, we discuss miRNAs serving as potential therapeutic targets to treat immunological conditions, particularly mucosal inflammation.

Keywords: Acute and chronic lung disease; Barrier function; Epithelial immune response; Epithelial inflammation; Inflammatory bowel disease; Mucosal immunity; Mucosal inflammation; Pulmonary inflammation; miRNA.

Fig. 1

MicroRNA biogenesis and function. Initially, in the nucleus miRNAs are generated as large transcripts called primary miRNAs (pri-miRNA) by RNA polymerase II (pol II). In the following step, a shorter hairpin structured, precursor miRNAs (pre-miRNA) is synthesized by RNase nuclease, Drosha associated with DiGeorge syndrome critical region 8 protein (DGCR 8). After exportation from the nucleus, cytosolic RNase nuclease Dicer further processes the hairpin-structured miRNA leading the unstable double-stranded short duplex miRNA. Here, only the mature strand gets incorporated into the RISC (RNA-silencing complex) for targeted gene repression. Functional repression of the target gene depends on miRNA-messenger RNA (mRNA) interaction in the 3′ untranslated region (3′ UTR) of the target mRNA. That way, one single miRNA can bind to many different mRNA targets and can therefore hold a wide regulatory impact. And, nonetheless, one target mRNA can be repressed by a variety of miRNAs, all together contributing to a robust miRNA-mediated regulation

Fig. 2

Immune challenges of mucosal organs. Together the lung and the intestine represent the main mucosal organs of the body. The large surface area is the main contact surface of the organism to the outside world. Being permanently exposed to diverse external factors including environmental antigens and commensal and pathogenic microbes, the mucosal surface can be seen as constantly “under fire”. A homeostatic mucosal environment is essential for keeping the balance between serving as a robust barrier and functioning as an exchange interface. Inflammatory metabolites and microbial products as well as impaired immune responses and bacterial translocation may affect this equilibrium, while an intact mucosal barrier together with the innate and adaptive immune system function to counter any disturbance

Fig. 3

Immune functions of microRNAs. MicroRNAs (miRNAs) contribute to the mucosal immunity on diverse levels. They orchestrate and modulate immune responses, such as regulating NF-κB pathways by miR-214 in the intestinal epithelium [65] or miR-16 which directly regulates the expression of TNFα and interleukin-6 in the pulmonary epithelium during acute lung injury [66]. MiRNAs take also control of the adaptive immune response, e.g., miR-146 represents an important regulator of the suppressive regulatory T cells (Tregs) in the intestine [67]. Intercellular communication between the immune cells and resident mucosa is also involving miRNAs. Neutrophil-epithelial transfer of miR-223 mediates critical anti-inflammatory regulatory signals during pulmonary inflammation (Neudecker et al., Neutrophil-epithelial miR-223 shuttling dampens acute lung injury. Science Translational Medicine, in press). Barrier integrity is another major component ensuring proper defense against any invading pathogens. Here miRNAs are involved in regulations affecting the mucosal barrier function. For example miR-21 and miR-122a directly influence mucosal permeability by regulating the expression of epithelial tight junctions [62, 63]. In later stages of mucosal inflammation including the resolution, remodeling and repair processes miRNAs are also critically involved and e.g., promote adequate recovery such as miR-101 which is important for proper lung recovery after lung injury [68]. Epithelial let-7d is essential in preventing remodeling and development of pulmonary fibrosis after inflammation and lung injury [69]. Similarly, miR-26a is acting in an anti-fibrotic manner [70, 71]

Fig. 4

Protective role of miR-223 in acute lung injury. During lung injury and pulmonary inflammation neutrophils (polymorphonuclear neutrophils, PMNs) are recruited to the sides of injury infiltrating the inflamed lung. Neutrophil derived miR-223 mediates anti-inflammatory signals by being secreted and transferred to alveolar epithelial cells. In the epithelium, miR-223 downregulates the pro-inflammatory target gene PARP-1, thereby dampening mucosal inflammation and cell injury (Neudecker et al., Neutrophil-epithelial miR-223 shuttling dampens acute lung injury. Science Translational Medicine, in press)

Fig. 5

Therapeutic inhibition of miR-214 in ulcerative colitis. During intestinal injury miR-214 is induced by IL-6 induced signal transducer and activator of transcription 3 (STAT3) (left side of the dotted line). Elevated miR-214 levels inhibit PDLIM2 (PDZ and LIM domain-containing protein) and PTEN (phosphatase and tensin homolog) representing direct miR-214 target genes. Inhibition of PDLIM2 and PTEN allow for phosphorylation of AKT (also protein kinase B, PKB), and finally activation of NF-κB. This pro-inflammatory pathway is triggered by a positive feedback loop aggravating and driving inflammation. Blocking miR-214 (right side of the dotted line) can break this feedback loop. Elevated PDLIM2 and PTEN level prevent phosphorylation of AKT, and consequently impede activation of NF-κB. In experimental colitis this therapeutic inhibition of miR-214 resulted in a lesser degree of severity of disease and reduced tumor growth in experimental colitis-associated cancer (CAC) [65]