Elevated Expression of C-Type Lectin Domain Family 5-Member A (CLEC5A) and Its Relation to Inflammatory Parameters and Disease Course in Adult-Onset Still’s Disease

Abstract

C-type lectin domain family 5-member A (CLEC5A) associates with adaptor DAP12 (DNAX activation protein 12) to form receptor complexes involved in inflammatory responses. We postulated a potential role of CLEC5A in the pathogenesis of adult-onset Still’s disease (AOSD) and aimed to investigate CLEC5A expression and its association with activity parameters and disease course. In 34 AOSD patients and 12 healthy controls (HC), circulating levels of CLEC5A-expressing monocytes or granulocytes were determined by flow cytometry analysis, the mRNA expression of CLEC5A and DAP12 on PBMCs by quantitative PCR, and plasma levels of proinflammatory cytokines by ELISA. AOSD patients had significantly higher percentages and mean fluorescence intensity (MFI) of CLEC5A-expressing monocytes (median 62.1% and 3.20, respectively) or granulocytes (72.6% and 3.22, respectively) compared with HC (in monocytes: 17.0% and 0.65, both p<0.001; in granulocytes: 67.3%, p<0.05 and 0.90, p<0.001; respectively). Patients also had significantly higher levels of CLEC5A mRNA expression on PBMCs compared with HC (median 1.77 vs. 0.68, p<0.05). The levels of CLEC5A-expressing monocytes or granulocytes were positively associated with activity scores and levels of IL-1β and IL-18 in AOSD patients. The patients with a systemic pattern had significantly higher levels of CLEC5A-expressing granulocytes and IL-18 compared to those with a chronic articular pattern of disease course. After 6 months of therapy, levels of CLEC5A-expressing monocytes and granulocytes significantly declined, paralleling the decrease of AOSD activity. Elevated CLEC5A levels and their positive association with activity parameters suggest that CLEC5A is involved in the pathogenesis and may serve as an activity indicator of AOSD.

An Update on the Pathogenic Role of Neutrophils in Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease

“…C–type lectin domain family 5–member A (CLEC5A), which combines with adapter proteins to form receptor complexes and which is involved in inflammatory responses through differentiation and activation of neutrophils, has been demonstrated to be overexpressed in AOSD patients. A positive correlation between CLEC5A levels and inflammatory parameters or disease activity of AOSD has also been reported in the literature [ 88 ]. The frequencies of circulating CD11b, the molecules of complement receptor 3, and CD32, most widely expressed in Fc γ R, were observed in whole blood cells of patients with AOSD than in patients with RA or healthy controls [ 89 ].…”

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

“…C-type lectin member 5A (CLEC5A) is a critical molecule that mediates lethal inflammatory responses induced by dengue virus [ 20 , 21 ], influenza viruses [ 22 ], Japanese encephalitis [ 23 ], and flavivirus [ 24 ]. CLEC5A is also involved in the pathogenesis of adult-onset Still’s disease [ 25 ] and dengue virus-activated osteoclast activation [ 26 ]. CLEC5A is expressed in immune cells, and CLEC5A activation triggers the burst release of proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) [ 20 , 27 ] and interleukin-6 (IL-6) [ 20 ].…”

Activation of the Innate Immune Checkpoint CLEC5A on Myeloid Cells in the Absence of Danger Signals Modulates Macrophages’ Function but Does Not Trigger the Adaptive T Cell Immune Response

“…In autoinflammatory disorders, like rheumatoid arthritis (RA) or Adult-onset Still's disease (AOSD), the percentage of CLEC5A-expressing monocytes and their level of CLEC5A expression (MFI) were significantly elevated as compared to healthy controls. Moreover, the CLEC5A expression positively correlated with the parameters of disease activity and with the secretion of proinflammatory cytokines, while it decreased after a therapy [25,26].…”