CISD2 Attenuates Inflammation and Regulates Microglia Polarization in EOC Microglial Cells—As a Potential Therapeutic Target for Neurodegenerative Dementia

Abstract

Background: Accumulating evidence has demonstrated a significant association between microglia-driven inflammation in the brain and neurodegenerative dementia. We previously showed a significant decline in CISD2 expression in mice models with advanced age. Moreover, we observed that the knockdown of CISD2 led to remarkable inflammation and mitochondrial dysfunction in neural cells. In the present study, we investigated whether CISD2 attenuation influences anti-inflammatory effects and M1-M2 polarization in microglia. Materials and Methods: The knockdown of CISD2 expression by siRNA (siCISD2) in EOC microglial cells was performed to mimic the age-driven decline of CISD2 expression. The extent of the inflammatory reaction, polarization in the M1/M2 spectrum, and NFκB activation were verified in EOC microglial cells exhibiting CISD2 deficiency. Results: In the cellular model of microglia, loss of CISD2 function mediated by siCISD2 exhibited a significant augmentation of proinflammatory signaling, as well as reduced expression levels of Arg-1, Ym1, IL-10, and BCL2. Attenuation of CISD2 expression led to a decrease in the proportion of the M2 phenotype of microglia (compared to M1). Enhanced DNA-binding activity of the NFκB p65 subunit was confirmed in cells transfected with siCISD2, as demonstrated by enzyme-linked immunosorbent assay (ELISA). Conclusions: To the best of our knowledge, this is the first report examining the following phenomena: (1) anti-inflammatory effects of CISD2 in microglia via NFκB regulation; and (2) microglial CISD2 assistance in the restoration of M2 microglia phenotype. The anti-inflammatory effects of CISD2 in microglia eventually augment anti-apoptotic effects, which provides a rationale for the development of potential therapeutic target for neurodegenerative diseases and neurodegenerative dementia.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

“…Inhibiting NADPH oxidase (Nox), which is responsible for producing ROS, drives microglia phenotype from M1 to M2 ( Babior, 1999 ; Choi et al, 2012 ). CDGSH iron-sulfur domain 2(CISD2), a longevity gene, exerts anti-inflammatory effects by inhibiting NF-κB signaling and preserving M2 microglia ( Lin, 2020 ). Toscano et al (2020) showed that postprandial triglyceride-rich lipoproteins (TRLs) could modulate microglia polarization in a fatty-acid-dependent manner: postprandial TRL-monounsaturated fatty acids promote M2 microglia polarization, whereas postprandial TRL-saturated fatty acids improve M1 microglia polarization.…”

The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

“…A CISD2 knockdown model using siCISD2 in immune and non-immune cells was applied to verify the potential function of CISD2. The following findings were revealed: (1) enhanced inflammatory responses (elevated production of iNOS and chemokine regulated on activation, normal T cell expressed and secreted [RANTES]), extensive mitochondrial dysfunction (including decreased mitochondrial membrane potential DeltaPsi(m) and elevated ROS release), promoted apoptosis, and decreased cell viability in neuron-like cells, SH-SY5Y [ 77 , 78 ]; and (2) augmented inflammatory reaction, as indicated in enhanced M1 microglia polarization (increased expression of TNF-α, IL-1β, iNOS, and COX2), attenuated M2 microglia phenotype (decreased expression of Arg-1, Ym1, and IL-10), and promoted apoptosis in EOC microglial cells [ 79 ].…”

“…Moreover, the anti-inflammatory effect of CISD2 has been shown to antagonize the activation of NFκB. Enhanced activity of NFκB p65 subunit DNA binding and subsequent nuclear translocation of NFκB p65 have been confirmed in siCISD2-transfected EOC microglial cells [ 79 ]. CISD2 inhibits NFκB signaling by acting upstream of the peroxisome proliferator-activated receptor (PPAR)-β (synonym: PPAR-δ), which is due to the decrease of PPAR-β expression shown in SH-SY5Y with CISD2 knockdown [ 80 ].…”

Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases

“…Our research team has demonstrated that CISD2 can block the stimulation of NFκB. Augmented DNA binding activity of the NFκB p65 subunit and nuclear translocation of NFκB p65 were verified in siCISD2-transfected EOC microglia (microglial cell lines) [ 46 ]. CISD2 slows down NFκB signaling by acting upstream of peroxisome proliferator-activated receptor (PPAR)-β [ 10 ].…”

“…Proinflammatory responses are demonstrated by the expressive levels of iNOS and RANTES in siCISD2-transfected neuron-like cells, SH-SY5Y [ 12 , 13 ]. Augmented inflammatory reactions are revealed by an increased M1 microglia polarization (increased expression of transforming necrosis factor-α, IL-1β, iNOS, and COX2), and decreased M2 microglia phenotype (decreased expression of Arg-1, Ym1, and IL-10) in siCISD2-transfected EOC microglial cells [ 46 ].…”