DNA hydroxymethylation in macrophages
Activated macrophages are found in the inflamed and hyperplasic synovial RA tissues. Macrophages are the main producers of high levels of pro-inflammatory cytokines such as TNFa and IL6. However, the mechanism of TNFa overexpression is still unknown. Recent findings showed that the 5-methylcytosine (5-mC) modification of DNA can be converted to 5-hydroxymethylcytosine (5-hmC) through the activation of the family of Ten-Eleven-Translocation (TET1-3) enzymes. We investigated the 5-hmC modification in macrophages stimulated with lipopolysaccharide (LPS) and characterized the function of TET1-3 enzymes during inflammation. Undifferentiated monocytes have the lowest levels of 5-hmC. It increases when monocytes differentiated into macrophages. This is accompanied by increases of 5-hmC at the TNF locus. Differentiated macrophages are stronger responders than monocytes in pro-inflammatory cytokines. Furthermore, upon LPS, 5-hmC showed a time-depend increase in the TNFa promoter. It was higher in macrophages than monocytes. TET1 inhibition reduced the stimulatory capacity of macrophages; this is associated with incapacity of increase 5-hmC at the TNF locus. Thus, TET1 contributes to the activation of macrophages through the regulation of 5-hydroxymethylation in the promoter of TNFa. TET1 could be a promising target to study in macrophages from RA patients.
Dr. Fangfang Sun and Prof. Shuang Ye, Department of Rheumatology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Baugarten Foundation, Zurich.