Background/Purpose: Dectin-1 is a c-type lectin like receptor that signals via syk and is involved in anti-fungal immunity. Dectin-1 was found to trigger experimental inflammatory arthritis, and likely play a role in the pathogenesis of some autoimmune diseases. This study aimed to examine (1) dectin-1 expression on circulating CD14+ monocytes in patients with systemic lupus erythematosus (SLE), (2) the effects of dectin-1 stimulation in ROS production by lupus monocytes and (3) Syk signaling and cytokine profile of dectin-1 stimulated lupus monocyte-derived dendritic cells (MDDCs).

Methods: SLE patients with active and inactive diseases and healthy subjects were recruited. MDDCs were derived from peripheral monocytes in the presence of IL-4 and GM-CSF. Dectin-1 agonists including curdlan, zymosan and toll-like receptor agonists Pam3CSK4 (TLR2) and LPS (TLR4) were used to stimulate monocytes and/or MDDCs. Dectin-1, ROS and phosphorylated-syk (p-Syk) were measured by flow cytometry. Cytokine profile was measured by and multi-bead immunoassay.

Results:  The percentage of dectin-1 expressing monocytes was significantly lower in active SLE patients (64.5+24.3%) compared to inactive patients (89.6+7.2%) and healthy controls (91.7+9.5%) (both p<0.001). The absolute count of dectin-1 expressing monocytes correlated significantly and inversely with SLEDAI (r=-0.40, p<0.001), anti-dsDNA antibody level (r=-0.29, p=0.004), C3 (r=0.35, p=0.001) and C4 (r=0.24, p=0.02). Despite this, ROS production upon stimulation by dectin-1 agonists was comparable between these 3 groups. Stimulation of dectin-1 led to activation and maturation of MDDCs with upregulation of HLA-DR and CD86 (all p<0.001). SLE MDDCs showed higher p-Syk activation compared to normal MDDCs upon dectin-1 stimulation (6.0+2.0 vs 2.8+1.0%, p<0.001). Curdlan-stimulated MDDCs produced higher levels of IL-1β, IL-23 and TNF-α. Adding TLR2 agonist to curdlan, SLE MDDCs produced significantly higher level of IL-1β (327.1+51.5 vs 125.3+88.5, p=0.009) and IL-6 (median 39.8 vs 21.7, p=0.03) compared to normal MDDCs. Combination of TLR4 agonist and curdlan induced IL-12 and TNF-α in normal MDDCs whereas lupus MDDCs produced predominant IL-6 and TNF-α.

Conclusion:  Active SLE patients had significantly lower circulating dectin-1 expressing CD14+ monocytes which produced comparable level of ROS upon stimulation compared to inactive patients and healthy subjects. Dectin-1 agonists led to activation, maturation and higher p-Syk activation in SLE MDDCs. Concomitant dectin-1 and TLR2 stimulation induced production of Th17 promoting cytokines, among which IL-1β and IL-6 were significantly higher in SLE compared to normal MDDCs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dectin-1-on-monocytic-cells-mediates-aberrant-innate-and-adaptive-immune-responses-in-patients-with-systemic-lupus-erythematosus/