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, 104 (3), 515-524

MicroRNA miR-223 as Regulator of Innate Immunity


MicroRNA miR-223 as Regulator of Innate Immunity

Xiaoyi Yuan et al. J Leukoc Biol.


MicroRNAs were discovered more than 2 decades ago and have profound impact on diverse biological processes. Specific microRNAs have important roles in modulating the innate immune response and their dysregulation has been demonstrated to contribute to inflammatory diseases. MiR-223 in particular, is very highly expressed and tightly regulated in hematopoietic cells. It functions as key modulator for the differentiation and activation of myeloid cells. The central role of miR-223 in myeloid cells, especially neutrophil and macrophage differentiation and activation has been studied extensively. MiR-223 contributes to myeloid differentiation by enhancing granulopoiesis while inhibiting macrophage differentiation. Uncontrolled myeloid activation has detrimental consequences in inflammatory disease. MiR-223 serves as a negative feedback mechanism controlling excessive innate immune responses in the maintenance of myeloid cell homeostasis. This review summarizes several topics covering the function of miR-223 in myeloid differentiation, neutrophil and macrophage functions, as well as in inflammatory diseases including acute respiratory distress syndrome and inflammatory bowel disease. In addition, nonmyeloid functions of miR-223 are also discussed in this review. Therapeutic enhancement of miR-223 to dampen inflammatory targets is also highlighted as potential treatment to control excessive innate immune responses during mucosal inflammation.

Keywords: inflammation; innate immune cells; miR-223; microRNA; myeloid development and activation.

Conflict of interest statement

Conflicts of interest: None


Figure 1.
Figure 1.. MiRNA biogenesis and modulation of target gene expression via diverse mechanisms
Biogenesis and functions of microRNA. Primary miRNAs (Pri-miRNA) are transcribed in the nucleus by RNA polymerase II (pol II). Pri-miRNAs are cleaved by Drosha complexed with DiGeorge syndrome critical region 8 protein (DGCR 8) to release precursor miRNAs (pre-miRNA). Then pre-miRNAs are transported to the cytosol and further processed by Dicer to reveal a double-stranded miRNA duplex. The mature strand of the miRNA duplex associates with the RNA silencing complex (RISC) to repress target mRNAs via binding to the 3’ untranslated region (3’UTR) region. MiRNAs achieve targeted gene repression via two major mechanisms: inhibition of mRNA translation and degradation of target mRNA. Additionally, recent studies suggest that miRNAs can also bind to 5’UTR region and promoter region of the mRNA target to achieve translation activation. In conclusion, the biogenesis of miRNAs is tightly regulated by specific cellular location and RNase to generate mature RNA. The main function of miRNAs is to modulate protein levels via diverse mechanisms. Adapted from Neudecker et al. MicroRNAs in mucosal inflammation [2]. J Mol Med (Berl).
Figure 2.
Figure 2.. Shuttling of miR-223 in acute respiratory distress syndrome.
MiR-223 protects tissue inflammation and injury in acute respiratory distress syndrome (ARDS). During mechanical ventilation or infection induced lung injury, neutrophils are recruited from the vasculature to the sites of pulmonary inflammation and tissue injury. Although highly expressed by myeloid cells, miR-223 is secreted in microvesicles from neutrophils upon pulmonary injury and then shuttled to alveolar type II epithelial cells (ATII) to confer lung protection. Once shuttled into ATII cells, miR-223 inhibits expression of poly(ADP-ribose) polymerase 1 (PARP-1) by directly targeting the 3’UTR region to dampen epithelial inflammation and tissue injury in acute lung injury. Nanoparticle-based delivery of miR-223 into the airway confers lung protection in murine models of acute lung injury. Future studies should focus on miR-223 as a promising therapeutic target for the treatment and prevention of ARDS. Adapted from Neudecker et al. MicroRNAs in mucosal inflammation [2]. J Mol Med (Berl).
Figure 3.
Figure 3.. MiR-223 in inflammatory bowel disease.
MiR-223 dampens intestinal inflammation in inflammatory bowel diseases. MiR-223 is induced in inflammatory monocytes during murine intestinal injury resulted from DSS exposure. Elevated miR-223 levels in inflammatory monocytes inhibit NLR family pyrin domain containing 3 (NLRP3), a direct miR-223 target gene. The inhibition of NLRP3 reduces inflammasome activity, and subsequently turns down IL-1b production. Reduced IL-1b levels result in amelioration of intestinal inflammation and improvement of clinical and histological signs of murine colitis. Therapeutic overexpression of miR-223 by systemic nanoparticle delivery decreeses disease severity in murine experimental colitis. Enhancing miR-223 therapeutically might serve as a promising treatment of inflammatory bowel disease to dampen intestinal inflammation [19].

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