br Funding Sources Support for this project was

Funding Sources Support for this project was provided to A.J.M. through grants from Susan G. Komen for the Cure,KG110601 and the Pennsylvania Department of Health, SAP #4100068718. G.C.P. and A.J.M. also receive financial support from NIH grants CA159337 and CA159315. No funding sources including pharmaceutical companies had any role in or provided any direct remuneration for the writing of this manuscript or the decision to submit it for publication.
Conflicts of Interest
Author Contributions
Acknowledgments
Introduction Interleukin 10 (IL-10) is a strong anti-inflammatory cytokine whose role was first reported as IFN-γ suppressing factor acting on Th1 Purmorphamine Supplier (Moore et al., 2001). It has since been shown that IL-10 signals through the IL-10 receptor (IL-10R), which is expressed on a variety of cells, especially many types of immune origin (Moore et al., 2001; Spencer et al., 1998; Tan et al., 1993). The IL-10R complex is composed of two different chains (IL-10R1 and IL-10R2). Binding of IL-10 to the IL-10R activates phosphorylation of the receptor associated Janus tyrosine kinases, resulting in STAT3-mediated signal transduction (Weber-Nordt et al., 1996; Wehinger et al., 1996). IL-10 also inhibit macrophage production of IL-12 (Moore et al., 2001). Recently, we and other groups have demonstrated that IL-10also suppresses Th17 cell differentiation (Franke et al., 2008). IL-10-deficient mice have been shown to spontaneously develop intestinal inflammation characterized by discontinuous transmural lesions affecting intestines, and by dysregulated production of proinflammatory cytokines including IL-12, IL-23, IFN-γ and IL-17(Berg et al., 1995; Kuhn et al., 1993). Several key features of theIL-10−/− chronic intestinal inflammation model are strikingly similar to human inflammatory bowel diseases. Many cell types, including macrophages, produce and respond to IL-10(Moore et al., 2001), but it is currently not understood precisely how IL-10 affects macrophage polarization, or the molecular mechanisms by which IL-10 regulates macrophage gene expressions in the development of inflammatory diseases. Macrophages are key regulators of both innate and adaptive immunity, serving as essential actors for both inflammatory responses to combat pathogen insult and tissue damage, as well healing responses that help repair affected tissue (Akira et al., 2013; Mills, 2012; Mosser and Edwards, 2008). Macrophages can be differentiated into classically activated macrophages (M1) or alternatively activated macrophages (M2) in response to certain microbial stimuli and/or cytokine signals (Akira et al., 2013; Tugal et al., 2013). M1 macrophages are believed to play an important role in the pathogenesis of various inflammatory diseases (Cassetta et al., 2011; Fernandez-Velasco et al., 2014; Mills, 2012). M1 macrophages produce numerous proinflammatory mediators such as tumor necrosis factor α (TNFα), interleukin-12 and 23, nitric oxide (NO), and other reactive oxygen species (ROS), which are required for host defense against pathogens (Mosser and Edwards, 2008).In contrast, M2 macrophages secrete significant amounts of IL-10 and polyamines, adapting immune responses to promote angiogenesis and tissue remodeling (Biswas and Mantovani, 2010). At the transcriptional level, M1 and M2 macrophages are regulated through different mechanisms, with IRF5 serving as a key transcription factor for M1 macrophage differentiation (Lu et al., 2015), while IRF4 is necessary for M2 macrophage differentiation (Krausgruber et al., 2011; Satoh et al., 2010). While recent work has unveiled many of the regulatory targets downstream of these transcription factors, some of the upstream factors that may modulate the expression or activity of these factors remains unknown. In this paper, we explore the role of an IL-10 induced microRNA as a post-transcriptional regulator of IRF5 expression. MicroRNAs (miRs) are small (22–24nt) non-coding RNA sequences that primarily function by interacting with the 3′UTRs of gene transcripts and suppressing their translation or driving their degradation (Baumjohann and Ansel, 2013; Friedman et al., 2009; Rebane and Akdis, 2013; Selbach et al., 2008). They are sequentially processed from longer transcripts by the ribo-nuclease III (RNase III) enzymes Drosha and Dicer, after which they exert their function by guiding the Argonaute (AGO) protein-containing miRNA-induced silencing complex (miRISC) to specific target mRNAs through complimentary pairing (Bartel, 2009; Fabian et al., 2010). miRs are integral in regulating gene expression in both innate and adaptive immune cells. Interestingly, recent studies demonstrated that IL-10 regulates the expression of several miRs, including miR187, miR-155, and miR-146a/b (Curtale et al., 2013) (McCoy et al., 2010). For instance, IL-10 can inhibit miR-155 expression induced by TLRs, and promote expression of anti-inflammatory genes (McCoy et al., 2010; O\'Connell et al., 2009). Curtale et al. reported that LPS induced expression of miR-146b via an IL-10-dependent loop and showed that miR-146b plays an anti-inflammatory role in human monocytes by direct targeting the TLR4 signaling pathway (Curtale et al., 2013).Despite these studies, the roles played by the IL-10-miRs axis in the control of macrophage orientation and inflammatory disease development remained poorly defined.