Tissue‐specific production of MicroRNA‐155 inhibits melanocortin 5 receptor‐dependent suppressor macrophages to promote experimental autoimmune uveitis

Abstract

Tissue-specific immune regulation is an important component of the immune response relevant to many areas of immunology. The focus of this study is on tissue-specific mechanisms that contribute to autoimmune uveitis. Precise gene regulation is necessary for the proper expression of an inflammatory or regulatory response. This precision gene regulation can be accomplished by microRNA at the level of the mRNA transcript. miR-155, in particular, has a complicated role in the immune response with positive and negative inflammatory effects. In this work, we identify a decrease in miR-155 in suppressor macrophages and further examine how tissue-specific production of miR-155 impacts experimental autoimmune uveitis. Importantly, we show that eliminating miR-155 expression by the target tissue before initiation reduces disease severity, but elimination of miR-155 after the onset of inflammation does not alter the course of disease. Additionally, expression of miR-155 by the target tissue before initiation is necessary for the induction of regulatory immunity that protects from further autoimmune disease, but not after the onset of inflammation. In summary, we find a MC5r-dependent decrease in miR-155 in postexperimental autoimmune uveitis APC, miR-155 production by the target tissue is necessary for the initiation of autoimmune uveitis, and may have a role in establishing protective regulatory immunity.Keywords: Autoimmunity r Experimental autoimmune uveitis r Macrophages r miR-155Additional supporting information may be found online in the Supporting Information section at the end of the article.

MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

“…Aberrant miRs expression has been reported in uveitis ( Kaneko et al., 2012 ; Muhammad et al., 2019 ; Puccetti et al., 2018 ; Wei et al., 2019 ). However, the molecular basis for miR dysregulation remains unclear.…”

Regulatory Mechanism of M1/M2 Macrophage Polarization in the Development of Autoimmune Diseases

“…miR-30b-5p is downregulated in the spleen, lymph nodes, and eye tissues of rats with autoimmune uveitis, and both in vitro and in vitro experiments have confirmed that supplementation with miR-30b-5p can reduce the level of IL-10 and TLR4-positive cells, thereby having a certain inhibitory effect on uveitis [ 95 ]. Meanwhile, miR-155 has been shown to promote M1 macrophage polarization and thus exert proinflammatory effects, showing remission to EAU after reducing miR-155 expression levels [ 67 , 96 ]. However, how miR-155 regulates the polarization of macrophages by regulating the expression of target genes and then affects the pathogenesis of uveitis needs to be further investigated.…”

Variability in the levels of exosomal miRNAs among human subjects could be explained by differential interactions of exosomes with the endothelium

“…10 Many miRNAs regulate up to hundreds of mRNAs, while their expression is tissuespecific. 11 Thus, due to their significant biological role as regulators of gene expression, miRNAs play an essential role both in physiological and pathophysiological processes. 12 MiRNAs carry unique properties such as their remarkable stability in plasma, their resistance to harsh conditions like boiling, low and high pH, RNases, long storage conditions as well as their withstanding of repetitive freezing and thawing cycles.…”

“…MiRNAs are short (~22 nucleotides in length) single‐stranded RNAs, that have been implicated in the regulation of gene expression by binding to target mRNAs in eukaryotic cells 9 modulating in this way various cellular functions including cell growth, proliferation, differentiation, and apoptosis 10 . Many miRNAs regulate up to hundreds of mRNAs, while their expression is tissue‐specific 11 . Thus, due to their significant biological role as regulators of gene expression, miRNAs play an essential role both in physiological and pathophysiological processes 12 …”