Journal Article

CXCR4 regulates macrophage M1 polarization by altering glycolysis to promote prostate fibrosis

Meng, Tong, Ma, Wenming, Chen, Xianguo, Feng, Rui, Xu, Wenlong, Zhang, Chen, Liang, Chaozhao, Zhang, Yi, Peng, Wei, Song, Jian, Chen, Jing

2024

Overview

Background C-X-C receptor 4(CXCR4) is widely considered to be a highly conserved G protein-coupled receptor, widely involved in the pathophysiological processes in the human body, including fibrosis. However, its role in regulating macrophage-related inflammation in the fibrotic process of prostatitis has not been confirmed. Here, we aim to describe the role of CXCR4 in modulating macrophage M1 polarization through glycolysis in the development of prostatitis fibrosis. Methods Use inducible experimental chronic prostatitis as a model of prostatic fibrosis. Reduce CXCR4 expression in immortalized bone marrow-derived macrophages using lentivirus. In the fibrotic mouse model, use adenovirus carrying CXCR4 agonists to detect the silencing of CXCR4 and assess the in vivo effects. Results In this study, we demonstrated that reducing CXCR4 expression during LPS treatment of macrophages can alleviate M1 polarization. Silencing CXCR4 can inhibit glycolytic metabolism, enhance mitochondrial function, and promote macrophage transition from M1 to M2. Additionally, in vivo functional experiments using AAV carrying CXCR4 showed that blocking CXCR4 in experimental autoimmune prostatitis (EAP) can alleviate inflammation and experimental prostate fibrosis development. Mechanistically, CXCR4, a chemokine receptor, when silenced, weakens the PI3K/AKT/mTOR pathway as its downstream signal, reducing c-MYC expression. PFKFB3, a key enzyme involved in glucose metabolism, is a target gene of c-MYC, thus impacting macrophage polarization and glycolytic metabolism processes.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Adenoviruses / AKT protein / Animals / Autoimmune diseases / B cells / Biomedical and Life Sciences / Bone marrow / c-Myc protein / Cancer / Cell Biology / Cell Polarity / Chemokine receptors / Chronic prostatitis / CXCR4 protein / Cytokines and Growth Factors / Disease / Ethylenediaminetetraacetic acid / Fertility / Fibroblasts / Fibrosis / G proteins / Genes / Glucose metabolism / Glycolysis / Health aspects / Humans / Inflammation / Kinases / Life Sciences / Macrophage / Macrophages / Macrophages - metabolism / Male / Mechanisms and Etiology of Male Health Disorders: Hormones / Membrane proteins / Metabolism / Mice / Mice, Inbred C57BL / Myc protein / Pain / Phosphatidylinositol 3-Kinases - metabolism / Phosphofructokinase-2 - genetics / Phosphofructokinase-2 - metabolism / Polarization / Prostate / Prostate - metabolism / Prostate - pathology / Prostatitis / Prostatitis - genetics / Prostatitis - metabolism / Prostatitis - pathology / Protein-Ligand Interactions / Proto-Oncogene Proteins c-akt - metabolism / Receptors / Receptors, CXCR4 - genetics / Receptors, CXCR4 - metabolism / Signal Transduction / TOR protein / TOR Serine-Threonine Kinases - metabolism / Urogenital system