Characterization of expression and function of dectin-1 on monocyte-derived dendritic cells in patients with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with diverse clinical manifestations on multiple organ systems. It is characterized by dysregulated innate and adaptive immunity. The exact pathogenesis of SLE is still unknown but current studies suggest the immunological abnormalities of lupus patients are triggered by environmental factors on genetically susceptible individuals. Dectin-1 is an innate immune receptor expressed on antigen presenting cells such as monocytes and dendritic cells (DCs). It is responsible for a wide range of cellular responses including the detection of pathogens, reactive oxygen species (ROS) production and induction of the potent inflammatory T helper 17 (Th17) cells. Excessive production of ROS and Th17 are associated with SLE pathogenesis. Interleukin-1β (IL-1β) is a crucial cytokine for the differentiation of Th17 and its production requires a two-step process: pro-IL-1β synthesis and IL-1β maturation by inflammasome. Both processes can be regulated by dectin-1 signaling mediated through spleen tyrosine kinase (Syk) phosphorylation. Recently, dectin-1 has been found to induce autoimmune arthritis in genetically susceptible mice and its ligand exacerbates disease development in a SLE mouse model. Therefore, we hypothesized that dectin-1 plays an important role in the immunopathogenesis of SLE involving the activation of inflammasome and production of pro-inflammatory cytokines. In the present study, the expressions and functions of dectin-1 were characterized on monocytes and monocyte-derived DCs (MDDC) from SLE patients. A diminished frequency of dectin-1^+ cells was found among total monocytes from lupus patients compared to normal controls. It was inversely correlated with disease activity and anti-dsDNA antibody levels suggesting factors related to disease activity may affect dectin-1 expression. However, soluble factors in sera from patients with active disease and high levels of anti-dsDNA antibodies failed to down-regulate dectin-1 expression on monocytes from normal controls. Despite the decreased expression of dectin-1 on SLE monocytes, the higher levels of ROS produced upon activation suggested functional hypersensitivity of dectin-1 in SLE patients. In contrary to monocytes, the expression of dectin-1 was comparable between patients and normal controls after differentiation into DC. While the production of cytokines was not different upon dectin-1 stimulation alone, SLE MDDC exhibited augmented dectin-1 signaling indicated by higher levels of Syk phosphorylation and pro-IL-1β synthesis. Furthermore, dectin-1 has been reported to interact with other immune receptors especially toll-like receptor 2 (TLR2). This study showed that co-activation of the two receptors led to significantly higher production of IL-1β and IL-6 on SLE MDDC compared to controls. In addition, elevated Syk phosphorylation in SLE MDDC was also observed suggesting abnormal cross-talk between dectin-1 and TLR2 signaling pathways in lupus patients. However, caspase-1 inflammasome activation was not different between patients and normal controls despite the higher levels of Syk phosphorylation. Therefore, the involvement of the non-canonical caspase-8 inflammasome requires to be further explored. In conclusion, the results from this study showed that dectin-1 is reduced in expression and functionally abnormal on SLE monocytes and MDDC. These findings provide a novel understanding on a role of dectin-1 in the complex pathogenesis of SLE.