Abstract
CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.
Highlights
CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators
Quantitative polymerase chain reaction (PCR) validation showed that the amounts of AHSP, Hemoglobin delta (HBD), and CA1 gene transcripts were larger in patients with systemic-onset juvenile idiopathic arthritis (SoJIA) than in healthy controls and those with Kawasaki disease (KD), bacteremia, oligo/polyarticular JIA, and systemic lupus erythematosus (Fig. 1a)
Co-culture with Peripheral blood CECs (PBCECs) did not increase the levels of galectin-3 or IL-18 binding protein (IL-18BP) in culture supernatants (Supplementary Fig. S4c,d online). These findings indicate the involvement of other molecules or direct cell–cell interaction in the immunosuppressive property of PBCECs obtained from SoJIA patients
Summary
CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. Systemic-onset juvenile idiopathic arthritis (SoJIA) is an autoinflammatory disorder of unknown etiology, characterized by spiking fever, lymphadenopathy, and generalized skin rash. No evidence has been produced for monogenic diseases involving the IL-1 and IL-18 pathways or any environmental factors associated with the development of SoJIA
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