Early Growth Response 1 Suppresses Macrophage Phagocytosis by Inhibiting NRF2 Activation Through Upregulation of Autophagy During Pseudomonas aeruginosa Infection

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients and immunocompromised individuals. A tightly regulated immune response possessed by healthy individuals can effectively control P. aeruginosa infections, whereas the patients with dysregulated immune response are susceptible to this bacterial pathogen. Early growth response 1 (Egr-1) is a zinc-finger transcription factor involved in regulation of various cellular functions, including immune responses. We previously identified that Egr-1 was deleterious to host in a mouse model of acute P. aeruginosa pneumonia by promoting systemic inflammation and impairing bacterial clearance in lung, which associated with reduced phagocytosis and bactericidal ability of leucocytes, including macrophages and neutrophils. However, the molecular mechanisms underlying the Egr-1-suppressed phagocytosis of P. aeruginosa are incompletely understood. Herein, we investigated whether the Egr-1-regulated autophagy play a role in macrophage phagocytosis during P. aeruginosa infection by overexpression or knockdown of Egr-1. We found that overexpression of Egr-1 inhibited the phagocytic activity of macrophages, and the autophagy activator rapamycin and inhibitor chloroquine could reverse the effects of Egr-1 knockdown and Egr-1 overexpression on phagocytosis of P. aeruginosa, respectively. Furthermore, the Egr-1-overexpressing macrophages displayed upregulated expression of autophagy-related proteins LC3A, LC3B and Atg5, and decreased levels of p62 in macrophages. Further studies revealed that the macrophages with Egr-1 knockdown displayed enhanced activation of transcription factor NRF2 and expression of scavenger receptors MACRO and MSR1. Altogether, these findings suggest that Egr-1 suppresses the phagocytosis of P. aeruginosa by macrophages through upregulation of autophagy and inhibition of NRF2 signaling.

Salmonella injectisome penetration of macrophages triggers rapid translation of transcription factors and protection against cell death

“…Consistent with our RNA-Seq and Ribo-Seq data, we found higher levels of Egr1 mRNA (Figure 2B) and protein in WT-infected cells at 60 min post WT Salmonella infection (Figure 2C-D). This upregulation was rapid but transient, consistent with previous reports 39, 40 . The abundance of mRNA peaked at 60 min and reduced to near baseline levels by 120 min.…”

Zinc finger transcription factor Egf1 promotes non-alcoholic fatty liver disease

“…Recently, Pang et al. 59 have made an interesting observation that Egr1 suppresses macrophage phagocytosis by reducing the expression of P62, thus depriving Nrf2, the master regulator of anti-oxidative transcription, a key co-factor. 59 Because increased ROS production and/or impaired ROS clearance is a hallmark event in NAFLD pathogenesis, 60 targeting Egr1 could certainly help restore redox homoeostasis in the liver.…”

Small extracellular vesicles derived from Nrf2-overexpressing human amniotic mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting NLRP3

“…Secondly, we speculate that the reduced expression of IL6 and TNFα is due to distinct macrophage subsets in the lung tissue. Meanwhile, studies have shown that Nrf2 activation increased the phagocytic ability of THP-1 macrophages [ 55 ], and inhibition of NRF2 signaling suppresses the phagocytosis of P. aeruginosa by RAW264.7 macrophages [ 56 ]. Therefore, we speculate also that Nrf2-Exo may promote M2 macrophage phagocytosis.…”