Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit

Abstract

Tumor-associated macrophages (TAMs), which display a tumor-supportive M2 phenotype, are closely related to tumor growth and metastasis. The reprogramming of TAMs toward a tumoricidal M1 profile has emerged as an attractive strategy for cancer immunotherapy. In this study, we found that the intratumoral injection of PcrV protein, a component of the Pseudomonas aeruginosa type 3 secretion system, suppressed tumor growth and increased apoptosis, inducible nitric oxide synthase (iNOS) expression, and the percentage of M1-polarized TAMs in tumor tissues. Furthermore, the intratumoral injection of PcrV-primed macrophages exerted a similar tumoricidal effect. In vitro analyses revealed that PcrV reeducated TAMs toward an antitumoral M1 phenotype and augmented their nitric oxide (NO)-mediated cytotoxicity against cancer cells. Mechanistically, we found that these effects were dependent on the activation of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated regulation of a PI3K/AKT/mTOR-glycolysis-NO feedback loop via direct interaction with TLR4. Collectively, these results revealed a potential role for PcrV in cancer immunotherapy through the targeting of TAM plasticity.

Lactylation of PKM2 Suppresses Inflammatory Metabolic Adaptation in Pro-inflammatory Macrophages

“…In recent years, insights into the critical role of metabolic adaptation in macrophage phenotype have emerged. [21] Studies have suggested that inhibition of glycolysis by 2-DG modulates macrophage polarization, increasing levels of ARG1 and decreasing expression of iNOS [19,55]. In addition, PKM2 is an essential molecular determinant of the Warburg effect and bridges metabolic and inflammatory functions [33,49].…”

Echinococcus multilocularis protoscoleces enhance glycolysis to promote M2 Macrophages through PI3K/Akt/mTOR Signaling Pathway

“…The secretion of the fourth-stage larval Angiostrongylus cantonensis inhibited glycolysis and induced to M2 macrophages through PI3K/Akt pathway [14]. Pseudomonas aeruginosa induced to M1 macrophages and increased glycolysis of tumor-associated macrophages ability [15].…”

“…Previous studies have found that numerous macrophages gathered around the lesion in AE patients, but the disease was still getting worse, and both M1 and M2 macrophages were signi cantly higher in close liver issue (CLT) than in distant liver tissue (DLT) from the lesion [12]. Pathogen infection modulated macrophages polarization through metabolic reprogramming by the PI3K/Akt/mTOR signaling pathway [14,15]. E. multilocularis infection changed glucose metabolism, macrophage polarization and PI3K/Akt/mTOR signaling pathways [11,12,16].…”

Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review)

“…On the one hand, a clinically used Toll-like receptor 4 agonist, monophosphatidyl lipid A, facilitated the transition from OXPHOS to glycolysis by activating mTOR signaling (63); on the other hand, Metformin (Met) shifted the state of TAMs to the M1 type by targeting and inducing a decrease in OXPHOS while increasing glycolysis (64). A Pseudomonas aeruginosa protein, PcrV, increased glycolytic activity and promoted the conversion of TAMs to the M1 type by activating the PI3K/AKT/mTOR signaling pathway, and the resulting increase in nitric oxide-related cytotoxicity induced Lewis lung carcinoma cell apoptosis (65). Furthermore, the anti-malarial drug chloroquine promotes the reprogramming of TAM metabolism from OXPHOS to glycolysis by increasing the lysosomal pH of macrophages, releasing Ca 2+ through the lysosomal Ca 2+ channel mucus-1, inducing the activation of p38 and NF-κB, and activating transcription factor EB (TFEB), which in turn polarizes TAMs from the M2 to the anti-tumor M1 phenotype (66).…”