Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

Abstract

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In RA, the synovial fluid of patients is enriched by a subset of DC that derive from monocytes (Mo-DC), which promote deleterious Th17 responses. The characterization of environmental factors in the joint that impact on the development and the fate of human Mo-DC is therefore of great importance in RA. When monocytes leave the blood and infiltrate inflamed synovial tissues, the process of differentiation into Mo-DC can be influenced by interactions with soluble factors such as cytokines, local acidosis and dysregulated synoviocytes. Other molecular factors, such as the citrullination process, can also enhance osteoclast differentiation from Mo-DC, favoring bone damages in RA. Conversely, biotherapies used to control inflammation in RA, modulate also the process of monocyte differentiation into DC. The identification of the environmental mediators that control the differentiation of Mo-DC, as well as the underlying molecular signaling pathways, could constitute a major breakthrough for the development of new therapies in RA.

Keywords: ACPA; abatacept; aryl hydrocarbon receptor; biotherapies; human dendritic cells; infliximab; rheumatoid arthritis; tocilizumab; tofacitinib.

Figure 1

Regulation of monocyte-derived dendritic cells differentiation and function by environmental factors in rheumatoid arthritis. Several environmental factors influence the differentiation of Mo-DC, such as the natural ligands of the aryl hydrocarbon receptor, the extracellular acidosis, or the GM-CSF produced by synovial CD4⁺ T cells. Interactions with synoviocytes can also affect the differentiation of Mo-DC as well as their maturation. Whether the program of monocyte differentiation into Mo-DC is already initiated within the monocyte, before its penetration into the synovial tissue is still unclear. Activated Mo-DC are potent inducers of Th17 cells that participate to cartilage destruction and chronic inflammation through the secretion of IL-17. Mo-DC can also transdifferentiate into osteoclasts, thus promoting bone loss. Abbreviations: AhR: Aryl hydrocarbon Receptor; GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor; M-CSF: Macrophage Colony-Stimulating Factor; Mo-DC: Monocyte-derived Dendritic Cells; RANKL: Receptor Activator of Nuclear factor Kappa-B Ligand.