Background/Purpose: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease of childhood, characterized by a predominance of mononuclear phagocytic effector cells, compared to the lymphocyte driven pathogenesis in other autoimmune JIA subtypes. Monocytes respond to their cytokine milieu by adopting polarization phenotypes with distinct functions, including M1 (classical) activation and several forms of alternative activation, including M2b and M2c which have potent immunoregulatory properties. Previous data has shown that monocytes in SJIA patients have a novel phenotype, with features of both classical activation and immunoregulatory phenotypes. Controlling factors of monocyte/macrophage differentiation in SJIA are unknown. MicroRNAs are transcriptional negative regulators which fine-tune gene expression, and have been implicated in the differentiation of monocytes/macrophages. However, microRNA expression in SJIA has not been examined. 

Methods: CD14+ monocytes were isolated from children with active SJIA and clinically inactive disease (CID), and miRNA expression quantified using TaqMan MicroRNA Array. Primary human monocytes or THP1 macrophage-like cells were polarized using LPS and interferon-γ (M1), IL-4 (M2a), LPS plus immune complexes (M2b), and IL-10 or TGF-β (M2c). THP1 cells were treated with either miR-125a-5p-specific or negative control antagomir or transfected with miR-125a-5p or negative control mimic prior to polarization. Gene expression was determined using real-time PCR or TaqMan assays.  

Results: We identified miR-125a-5p as the most highly upregulated microRNA in monocytes from children with active SJIA compared to those with CID. Expression of miR-125a-5p significantly correlated with markers of disease activity, including serum ferritin and white blood cell count, and systemic features such as rash and hepatomegaly. Expression of miR-125a-5p was significantly increased in both primary human monocytes and THP1 cells after polarization with M2b or M2c conditions, but not by M1 polarization. Interestingly, we found that miR-125a-5p was dispensable for M1 polarization, as treatment with a specific microRNA antagomir did not alter expression of MIG, I-TAC, TNF-α or IL-6. However, miR-125a-5p was essential for M2b polarization, as antagomir treatment significantly reduced expression of the M2b-specific chemokine CCL1 by 56%. Conversely, transfection of miR-125a-5p mimic resulted in enhanced M2b polarization with increased expression of CCL1, IL-6, and CD163. In contrast, miR-125a-5p overexpression diminished M2c polarization, and altered M1 polarization by increasing production of some M2-associated markers.

Conclusion: Our data demonstrated increased miR-125a-5p expression in active SJIA and correlation with disease activity. We also showed that miR-125a-5p serves as an essential regulator of the polarization of M2b regulatory macrophages, and may impact the balance between different forms of alternative activation. Taken together, these data suggest that miR-125a-5p could serve as an important diagnostic and therapeutic target in SJIA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microrna-125a-5p-has-increased-expression-in-active-systemic-juvenile-idiopathic-arthritis-and-is-an-essential-modulator-of-regulatory-macrophage-phenotypes-in-vitro/