MicroRNA networks associated with active systemic juvenile idiopathic arthritis regulate CD163 expression and anti-inflammatory functions in macrophages through two distinct mechanisms

Abstract

Summary sentence: MicroRNAs utilize multiple mechanisms to regulate CD163 expression and integrate well-characterized macrophage phenotypes and functional properties seen in active systemic juvenile idiopathic arthritis. AbstractSystemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro-and anti-inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti-inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro-inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly up-regulated by IL-10 (M(IL-10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA plays key roles in integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNAs regulate macrophage functional responses in SJIA including CD163 expression. We find that 2 microRNAs previously found to be elevated in active SJIA, miR-125a-5p and miR-181c, significantly reduced macrophage CD163 expression through 2 distinct mechanisms. Neither microRNA was elevated in M(IL-10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir-181 species directly targeted CD163 mRNA for degradation. In contrast, miR-125a-5p functions indirectly, as transcriptome analysis of miR125a-5p overexpression identified "cytokine-cytokine receptor interactions" as the most significantly repressed gene pathway, including decreased IL10RA, required for IL-10-mediated CD163 expression. Finally, overexpression of miR-181c inhibited CD163 anti-inflammatory responses to hemoglobin or high mobility group box 1 (HMGB1) complexes. Together, these data show that microRNA utilizes multiple mechanisms to integrate well-characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.

Systemic Juvenile Idiopathic Arthritis–Associated Lung Disease: Characterization and Risk Factors

“…Cytokine concentrations in BAL fluid were determined using Milliplex Multiplex kits (MilliporeSigma) , except for IL‐18, which was determined using specific ELISA kits obtained from MBL.…”

The Immunology of Macrophage Activation Syndrome

“…Similarly, other reports have shown that CD163 + macrophages have anti-inflammatory M2 properties. The anti-inflammatory cytokine IL-10 was found to upregulate the expression of CD163 expression on macrophages (72). In addition, CD163 + macrophages are thought to play a protective role during inflammation due to their ability to clear free-hemoglobin (Hgb).…”

The Multi-Omics Architecture of Juvenile Idiopathic Arthritis

“…The miR-181s may target directly at CD163 mRNA for degradation. Overexpression of miR-181c inhibits the anti-inflammatory response of CD163 to hemoglobin or the high-mobility box 1 complex [ 110 ]. In contrast, transcriptome analysis of miR-125a-5p overexpression identified “cytokine–cytokine receptor interactions” as the most significantly inhibited gene pathway with reduced interleukin 10 Receptor Subunit Alpha ( IL10RA ), while IL-10 mediation is required for CD163 expression [ 108 ].…”