Aberrant expression of
long non-coding RNA (
lncRNA) H19 is tightly linked to multiple steps of
tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of
lncRNA H19 in macrophages remain obscure. To investigate whether
lncRNA H19 modulates macrophage activation in
rheumatoid arthritis (RA),
lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in
lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced
arthritis mouse model. The level of
lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of
lncRNA H19 altered
lipopolysaccharide plus
interferon-induced M1 macrophage polarization and decreased
IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients.
LncRNA H19 overexpression markedly induced
IL-6, CD80,
HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated
arthritis in mice by promoting M1 macrophage polarization along with iNOS,
IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle.
GSK-J4, an inhibitor of KDM6A, suppressed the activity of
lncRNA H19 in macrophages and ameliorated
lncRNA H19-aggravated
arthritis. In summary, the current study demonstrated that
lncRNA H19 is upregulated in RA patients and arthritic mice.
LncRNA H19 promotes M1 macrophage polarization and aggravates
arthritis by upregulating KDM6A expression.