Abstract
Monocyte-derived Dendritic cells (Mo-DC) are a distinct DC subset, involved in inflammation and infection, they originate from monocytes upon stimulation in the circulation and their activation and function may vary in autoimmune diseases. In this study we investigate the differences in Mo-DC differentiation and function in patients with Rheumatoid (RA) compared to Psoriatic arthritis (PsA). A significant increase in the Mo-DC differentiation marker CD209, paralleled by a corresponding decrease in the monocytic marker CD14, was demonstrated in RA compared to PsA, as early as 1 day post Mo-DC differentiation. RA monocytes ex-vivo were phenotypically different to PsA, displaying a more mature phenotype associated with altered cellular-morphology, early dendrite formation, and a significant increase in the CD40 marker. In addition, SPICE algorithm flow cytometric analysis showed distinct differences in chemokine receptors distribution in HC compared to PsA and RA CD14+ cells in the blood, with increased expression of the chemokine receptors CCR7 and CXCR4 observed in PsA and RA. In addition CD14+ cells at the site of inflammation showed a different chemokine receptor pattern between PsA and RA patients, with higher expression of CXCR3 and CXCR5 in RA when compared to PsA. The early priming observed in RA resulted in monocyte-endocytosis and antigen-uptake mechanisms to be impaired, effects that were not observed in PsA where phagocytosis capacity remained highly functional. Tofacitinib inhibited early Mo-DC differentiation, decreasing both CD209 and CD40 activation markers in RA. Inhibition of Mo-DC differentiation in response to Tofacitinib was mediated via an imbalance in the activation of NADPH-oxidases NOX5 and NOX2. This effect was reversed by NOX5 inhibition, but not NOX2, resulting in suppression of NOX5-dependent ROS production. In conclusion, RA monocytes are already primed ex vivo to become DC, evident by increased expression of activation markers, morphological appearance and impaired endocytosis capacity. Furthermore, we demonstrated for the first time that NOX5 mediates Mo-DC differentiation and function in response to Tofacitinib, which may alter DC functions.
Highlights
Dendritic cells (DCs) are a heterogeneous population of professional antigen-presenting cells at the interface of innate and adaptive immunity [1, 2]
Monocyte differentiation into DC is driven by multiple signals, including NADPH oxidases (NOX) which play a key role in both Monocyte-derived Dendritic cells (Mo-DC) differentiation and antigen presentation, with NOX5 identified as a key regulator of Mo-DC development in healthy subjects [8]
We observed that monocytes were fully differentiated to Mo-DC in HC, Psoriatic arthritis (PsA) and Rheumatoid arthritis (RA) when analyzed at the end of the differentiation process
Summary
Dendritic cells (DCs) are a heterogeneous population of professional antigen-presenting cells at the interface of innate and adaptive immunity [1, 2]. DCs are classified according to their tissue location and function [3], a specific subset of DCs derived from monocytes (Mo-DC) have a key role in inflammation [4] and infection [5], often termed “inflammatory Mo-DC” [6]. While conventional DCs are critical for self-tolerance and for triggering specific immunity, inflammatory DCs are mainly involved in innate defenses and T-cell activation [7]. Abundant expression of DC have been observed in the synovium of RA and PsA patients in comparison to osteoarthritis [11, 17], with studies demonstrating their ability to guide differentiation of naive T cells in an antigen-specific manner [18]. To date few studies have examined Mo-DC in inflammatory arthritis in relation to disease pathogenesis, disease progression or therapeutic response
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