A Potential Role of Myeloid DAP12-Associating Lectin (MDL)-1 in the Regulation of Inflammation in Rheumatoid Arthritis Patients

Shie-Liang Edmond Hsieh,Chi-Chen Lin,Ling Yao,Szu-Ting Chen,Kui-Chou Huang,Yi-Ming Chen,Oliver Frey,Joung-Liang Lan,Der-Yuan Chen

doi:10.1371/journal.pone.0086105

Abstract

The pathogenic roles of myeloid DAP12-associating lectin-1(MDL-1) and DAP12 in human rheumatoid arthritis (RA) remain unknown. Frequencies of MDL-1-expressing monocytes in 22 active RA patients, 16 inactive RA patients, 12 osteoarthritis (OA) patients and 10 healthy controls (HC) were determined by flow-cytometry analysis. The mRNA expression levels of MDL-1 and DAP12 on PBMCs were evaluated by quantitative PCR, and their protein expression levels in the synovium were examined by immunohistochemistry. Significantly higher median percentages of circulating MDL-1-expressing monocytes were observed in active RA patients (53.6%) compared to inactive RA patients (34.1%), OA patients (27.9%), and HC (21.2%). Levels of MDL-1 and DAP12 gene expression in PBMCs and their protein expression in the synovium were significantly higher in active RA patients than in inactive RA or OA patients. MDL-1 levels were positively correlated with parameters of disease activity, articular damage, and levels of proinflammatory cytokines. MDL-1 activator (Dengue virus type 2 antigen) stimulation on PBMCs resulted in significantly enhanced levels of proinflammatory cytokines in RA patients compared to those in OA patients or HC, indicating that MDL-1 activation is functional. Frequencies of MDL-1-expressing monocytes and levels of MDL-1 and DAP12 gene expression significantly decreased after effective therapy. Concordant overexpression of MDL-1 and DAP12 were correlated with increased production of proinflammatory cytokines in RA patients, suggesting their roles in regulating articular inflammation.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the infiltration of macrophages and T cells into the joints, synovial hyperplasia, and bone erosions associated with excessive osteoclast activity [1,2]
To explore the functional role of Myeloid DNAX activation protein 12 (DAP12)-Associating Lectin (MDL)-1 activation which may have a possible link with DAP12 and inflammatory response in human RA; we examined changes in mRNA expression levels and supernatant levels of downstream cytokines on peripheral blood mononuclear cells (PBMCs) treated with Myeloid DAP12-associated lectin-1 (MDL-1) activator using a method modified from previous reports [34]
Significantly higher mean fluorescence intensity (MFI) of MDL-1 staining on monocytes was observed in active RA patients compared to inactive RA patients, OA patients, or healthy control subjects (Figure 1C)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the infiltration of macrophages and T cells into the joints, synovial hyperplasia, and bone erosions associated with excessive osteoclast activity [1,2]. Macrophage-derived proinflammatory cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, are crucial mediators in rheumatoid synovitis and subsequent bone destruction in RA [5,6]. IL-17A can stimulate monocytes to produce proinflammatory cytokines, and amplify the inflammatory cascade [7]. Accumulating evidence shows that alterations in proinflammatory cytokines are viewed as both a possible important pathogenic factor and a potential target for therapeutic intervention in RA [9,10,11,12,13]

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