LAIR-1 shedding from human fibroblast-like synoviocytes in rheumatoid arthritis following TNF-α stimulation

Summary

This study examined the expression of the inhibitory receptor, leukocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1) in fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients to investigate its potential role in the modulation of inflammatory cytokines, metalloproteinases (MMPs), and invasiveness of synoviocytes. LAIR-1 expression in synovial tissues from RA patients, osteoarthritis patients, and healthy donors was analyzed by immunohistochemistry. The membrane-bound form (mLAIR-1) was detected by flow cytometry. Factors involved in inflammation and MMP activity in FLS were analyzed by qPCR. LAIR-1 expression was higher in the synovia of the RA patients than those of the osteoarthritis patients. Co-immunostaining of vimentin/LAIR-1 demonstrated that LAIR-1 was mainly localized in FLS in the RA patients. Surprisingly, primary FLS isolated from the RA patients had low levels of mLAIR-1 expression, with cytoplasmic distribution. The extracellular domain of LAIR-1 was shed from the cell surface in response to TNF-α, and this process could be blocked by serine protease inhibitors. Additional experiments indicated that LAIR-1 overexpression considerably reduced FLS invasion, which simultaneously reduced the mRNA levels of IL-6, IL-8, and MMP-13 in the presence of TNF-α. Our study demonstrated that LAIR-1 is an anti-inflammatory molecule, and it was upregulated in FLS in the RA patients; however, cell-surface LAIR-1 could be shed from cells in the inflammatory microenvironment in RA. This may weaken the interaction of LAIR-1 with its ligand, thus reducing the anti-inflammatory effects of LAIR-1. These findings suggested that LAIR-1 may be an important factor involved in the mediation of the progressive joint destruction in RA. This article is protected by copyright. All rights reserved.