Abstract
Monocytic cells exhibit a high level of heterogeneity and have two distinct modes of their activation: 1) classical M1 path associated with inflammation and tissue damage, and 2) alternative M2 path. Although it has been demonstrated that M2 macrophages play an important role in the regulation of the allergic immune responses, tissue maintenance and repair, little is known about the mechanisms that determine the M2 phenotype. We have previously shown that miR-124 is expressed in microglia that exhibit the M2 phenotype and overexpression of miR-124 in macrophages resulted in downregulation of a number of M1 markers (MHC class II, CD86) and up-regulation of several M2 markers (Fizz1, Arg1). We further investigated whether the polarization of macrophages towards the M2 phenotype induced miR-124 expression. We found that exposure of cells to IL-4 and IL-13 resulted in the upregulation of miR-124 in macrophages. We also demonstrated that IL-4 induced expression of three miR-124 precursor transcripts with predominant expression of pri-miR-124.3, suggesting regulation of miR-124 expression by IL-4 on a transcriptional level. Expression of miR-124 in microglia did not depend on IL-4 and/or IL-13, whereas expression of miR-124 in lung resident macrophages was IL-4 and IL-13-dependent and was upregulated by systemic administration of IL-4 or during allergic inflammation. Upregulation of several M2 markers (CD206, Ym1) and downregulation of the M1 markers (CD86, iNOS, TNF) in M2-polarized macrophages was abrogated by a miR-124 inhibitor, suggesting that this microRNA contributed to the M2 phenotype development and maintenance. Finally we showed that human CD14+CD16+ intermediate monocytes, which are found in increased numbers in patients with allergies and bronchial asthma, expressed high levels of miR-124 and exhibited other properties of M2-like cells. Thus, our study suggests that miR-124 serves as a regulator of the M2 polarization in various subsets of monocytic cells both in vitro and in vivo.
Highlights
Monocytic cells represent a complex and heterogeneous population of cells that include tissue resident macrophages nested in various tissues including the central nervous system (CNS), peritoneum, lungs, liver, and adipose tissue [1]
We have previously found that transfection of macrophages with miR-124 resulted in downregulation of the M1-associated genes, such as TNF, MHC class II, and CD86, while at the same time upegulating the M2-associated genes Fizz1, Arg1, and TGFb1 [15]
The peritoneal macrophages from B6 mice at their M0 state expressed high levels of IL-4 when compared to the bone marrow (BM)-derived macrophages of the same mouse strain or the ex-vivo isolated adult microglia, which was shown to be of the M2 phenotype [8] (Fig. S1A)
Summary
Monocytic cells represent a complex and heterogeneous population of cells that include tissue resident macrophages nested in various tissues including the central nervous system (CNS), peritoneum, lungs, liver, and adipose tissue [1]. In addition to the tissue resident macrophages, there is a mobile population of monocytes circulating in the peripheral blood that have an ability to transmigrate into tissues during inflammation and differentiate to the inflammatory macrophages [2]. The classically activated M1 macrophages express and secrete large amounts of potent pro-inflammatory mediators such as TNF and reactive oxygen species (such as NO) that are associated with substantial tissue damage. The M2 macrophages produce a number of factors that are responsible for the anti-parasitic response and promote tissue repair such as Fizz, Ym1, Arg, Mannose Receptor (MR or CD206) as well as anti-inflammatory, regulatory, and B cell-stimulating factors such as TGF-b1, IL-4, and IL-10 [6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
