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.

Po-Ku Chen,Shie-Liang Hsieh,Der-Yuan Chen,Shih-Hsin Chang,Joung-Liang Lan,Chi-Chen Lin

doi:10.1155/2020/9473497

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.

Highlights

Adult-onset Still’s disease (AOSD) is characterized by spiking fever, skin rash, arthritis, multisystemic involvement, neutrophilic leukocytosis, and elevated levels of acute phase reactants [1,2,3], and the affected tissues, such as skin, show influx of neutrophils [4]
There were no significant differences in the demographic data between AOSD patients and healthy controls (44:8 ± 9:8 years; 9 women and 3 men)
The representative cytometric histograms of C-type lectin domain family 5-member A (CLEC5A) expression on monocytes or granulocytes were obtained from one active AOSD patient (Figure 1(a) A and B) and one healthy subject (Figure 1(b) A and B), respectively

Summary

Introduction

Adult-onset Still’s disease (AOSD) is characterized by spiking fever, skin rash, arthritis, multisystemic involvement, neutrophilic leukocytosis, and elevated levels of acute phase reactants [1,2,3], and the affected tissues, such as skin, show influx of neutrophils [4]. Journal of Immunology Research inhibitors [8] suggests the critical role of IL-1β-related inflammasome in its pathogenesis. Resonating with this finding, we recently revealed an elevated expression of NLRP3inflammasome signaling in AOSD patients [9]. Our previous study revealed elevated CLEC5A expression on peripheral mononuclear cells (PBMCs) and inflamed synovium in patients with rheumatoid arthritis (RA) [12]. Aoki et al reported that mouse macrophages and neutrophils had significantly increased expression of CLEC5A, which played an important role in innate immunity [11]. Given the neutrophilic leukocytosis and elevated expression of NLRP3-inflammasome characteristic of AOSD [9], we hypothesize an important role of CLEC5A in AOSD pathogenesis

Methods

Results

Discussion

Conclusion