Systemic lupus erythematosus is associated with impaired autophagic degradation via interleukin-6 in macrophages
Journal
Biochimica et Biophysica Acta - Molecular Basis of Disease
Journal Volume
1867
Journal Issue
2
Date Issued
2021
Author(s)
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with dysregulated interleukin (IL)-6 and autophagy. Although such disturbances are increasingly recognized in patients with SLE and animal models of the disease, little is known about the specific role of IL-6 and autophagy in SLE macrophages. Here, we investigated alterations in the IL-6 axis and autophagy in macrophages derived from patients with SLE and determined whether IL-6 modulates autophagy using human macrophage models. Serum IL-6 detected by ELISA was higher in SLE patients (n = 19) than in normal controls (n = 19, p < 0.001). Levels of the IL-6 receptor (IL-6R) and autophagic markers LC3B and p62 in SLE and normal macrophages were assessed by real-time PCR, western blotting, and immunofluorescence. Compared with normal macrophages, SLE macrophages not only overexpressed IL-6Rs but also exhibited impaired autophagic degradation as evidenced by elevated levels of LC3B and p62. In vitro analyses using macrophage models revealed that prolonged exposure to exogenous recombinant human IL-6 induced a marked impairment of autophagic degradation indicated by elevated levels of LC3B and p62 in both primary macrophages and transformed macrophages. Pretreatment with tocilizumab, a humanized anti-IL-6R monoclonal antibody, restored autophagic degradation and reversed p62 accumulation in a paracrine manner in macrophages. These findings demonstrate that SLE involves IL-6-induced impairment of autophagic degradation through augmentation of IL-6R in human macrophages. ? 2020 Elsevier B.V.
Subjects
IL-6/IL-6R axis; Impairment of autophagic degradation; Macrophages; Systemic lupus erythematosus; Tocilizumab
SDGs
Other Subjects
interleukin 6; interleukin 6 receptor; microtubule associated protein 1; microtubule associated protein 1 light chain 3B; recombinant interleukin 6; sequestosome 1; tocilizumab; unclassified drug; IL6 protein, human; IL6R protein, human; interleukin 6; interleukin 6 receptor; MAP1LC3B protein, human; microtubule associated protein; monoclonal antibody; P62 protein, human; recombinant protein; RNA binding protein; Article; autophagic degradation; autophagy (cellular); clinical article; controlled study; enzyme linked immunosorbent assay; gene overexpression; human; human cell; immunofluorescence; in vitro study; light chain; macrophage; paracrine signaling; pathogenesis; priority journal; protein expression; real time polymerase chain reaction; systemic lupus erythematosus; Western blotting; autophagy; blood; case control study; cell culture; drug effect; immunology; macrophage; metabolism; normal human; primary cell culture; severity of illness index; systemic lupus erythematosus; THP-1 cell line; Antibodies, Monoclonal, Humanized; Autophagy; Case-Control Studies; Cells, Cultured; Healthy Volunteers; Humans; Interleukin-6; Lupus Erythematosus, Systemic; Macrophages; Microtubule-Associated Proteins; Paracrine Communication; Primary Cell Culture; Receptors, Interleukin-6; Recombinant Proteins; RNA-Binding Proteins; Severity of Illness Index; THP-1 Cells
Publisher
Elsevier B.V.
Type
journal article