Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Involved in Inflammation by Negatively Regulating the NF-κB Pathway

Abstract

Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.

Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles

“…MANF can also repress proliferation of inflammatory fibroblast-like synoviocytes in a rodent methylated bovine serum albumin-induced arthritis model 29 . Furthermore, MANF can alleviate oxygen–glucose deprivation-induced cell damage and inflammation in rat primary astrocytes 61 , as well as suppress lipopolysaccharide-induced inflammatory response in neural stem cells 62 .…”

“…It has been shown that the small C-terminal domain is responsible for the intracellular protection against the Bax-dependent apoptosis in the sympathetic superior cervical ganglion (SCG) neurons 27 . It has also been shown that the C-terminal SAP-like domain of MANF interacts with the DNA binding domain of NF-κB p65 subunit after translocation of MANF into nucleus under inflammation and ER stress, which negatively regulates NF-κB signaling 29 . MANF contains eight conserved cysteines that form four intramolecular disulfide bonds including two in CXXC sequences 28 .…”

“…In vitro , MANF expression is upregulated in cell lines derived from bone tissue (U2OS), kidneys (HEK293), neuroblastoma (SH-SY5Y) and embryo fibroblasts (NIH 3T3) in response to ER stress triggered by tunicamycin (TM), thapsigargin (TG), and lactatystin 26, 33 . In vivo , MANF expression is induced in chondrocytes following ER retention of the mutant cartilage extracellular matrix protein in mouse knock-in models of chondrodysplasia caused by matrilin-3 or type × collagen mutations 34 , in pancreatic β cells following misfolding of mutant proinsulin in Akita mouse model carrying an insulin C96Y mutation 26 , and in synoviocytes following inflammation mediated-ER stress in a rabbit antigen-induced arthritis model 29 . MANF expression is also increased in response to ischemia-induced ER stress both in vitro and in vivo 32, 33, 35–37 .…”

“…Chen LJ. et al reports that compared with healthy controls, MANF mRNA is dramatically upregulated in peripheral white blood cells from patients with autoimmune inflammatory disease, including rheumatoid arthritis and systemic lupus erythematosus 29 . Galli E. et al shows that high serum MANF concentrations are found in children 1–9 years of age close to the diagnosis of type 1 diabetes (T1D), but not in older children and adolescents 10–17 years of age with recent onset T1D or adults with longer-term T1D 39 .…”

“…Recent data demonstrate that MANF in the nucleus interferes with the binding of NF-κB p65 subunit to its target gene promoters and subsequently suppresses the expression of NF-κB-dependent inflammatory genes 29 . MANF also inhibits p38 mitogen activated protein kinase (MAPK) pathway 62 .…”