Inhibition of fucosylation reshapes inflammatory macrophages and suppresses type II collagen-induced arthritis.

Abstract

OBJECTIVE:

Fucosylation catalyzed by fucosyltransferases (FUTs) is an important posttranslational modification involved in a variety of biologic processes. This study was undertaken to determine the roles of fucosylation in rheumatoid arthritis (RA) and to assess the efficacy of reestablishing immune homeostasis with the use of 2-deoxy-d-galactose (2-d-gal), a fucosylation inhibitor.

METHODS:

Quantitative polymerase chain reaction was performed to determine the expression of FUT genes in synovial tissue from RA and osteoarthritis (OA) patients and in fluorescence-activated cell-sorted cells from RA synovial fluid. The in vivo inhibitory effect of 2-d-gal was evaluated in a murine collagen-induced arthritis (CIA) model. The in vitro effects of 2-d-gal on differentiation of inflammatory macrophages, production of cytokines, and antigen uptake, processing, and presentation functions were analyzed.

RESULTS:

FUTs that are involved in terminal or subterminal fucosylation, but not those involved in core fucosylation or O-fucosylation, were up-regulated in RA compared to OA synovial tissue. The expression of terminal FUTs was highly positively correlated with the expression of TNF (encoding for tumor necrosis factor α). Terminal FUTs were predominantly expressed in M1 macrophages. In vivo, 2-d-gal treatment of mice precluded the development of CIA by reducing inflammatory macrophages and Th17 cells in the draining lymph nodes and decreasing the levels of TNFα, interleukin-6 (IL-6), and antibodies to type II collagen in the serum. In vitro, treatment with 2-d-gal skewed the differentiation of M1 macrophages to IL-10-producing M2 macrophages. Furthermore, 2-d-gal significantly inhibited the antigen-presenting function of M1 macrophages.

CONCLUSION:

Terminal fucosylation is a novel hallmark of inflammatory macrophages. Inhibition of terminal FUTs reshapes the differentiation and functions of M1 macrophages, leading to resolution of inflammation in arthritis.

• Authors: Jun Li, Hui-Chen Hsu, Yana Ding, Hao Li, Qi Wu, PingAr Yang, Bao Luo, Amber L Rowse, David M Spalding, S Louis Bridges Jr, John D Mountz
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 66 Issue 9 Pg. 2368-79 (Sep 2014) ISSN: 2326-5205 [Electronic] United States
• PMID: 24838610 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American College of Rheumatology.

Chemical References

• 2-deoxy-lyxo-hexose
• Galactose

Topics

• Adult
• Aged
• Animals
• Arthritis, Experimental (drug therapy, metabolism, pathology)
• Arthritis, Rheumatoid (metabolism, pathology)
• Female
• Galactose (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mice
• Middle Aged
• Osteoarthritis (metabolism, pathology)
• Synovial Membrane (drug effects, metabolism, pathology)