USP18-driven macrophage M2 polarization through fatty acid β-oxidation inhibits immune responses induced by RSV infection.

INTRODUCTION

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory infections in infants under six months, with limited treatment options available. Macrophages play a pivotal role in antiviral immunity, where their polarization state directly modulates immune responses.

METHODOLOGY: The expression changes of ubiquitin-specific protease 18 (USP18) in RSV-infected samples were analyzed through the Gene Expression Omnibus database. An RSV infection model was established in C57BL/6 mice, and USP18 expression in lung tissues was measured by quantitative polymerase chain reaction (qPCR). Adenovirus-mediated USP18 knockdown was performed via tail vein injection, and its effects on immune cells were assessed using enzyme-linked immunosorbent assay (ELISA) and qPCR. THP-1 macrophage models with USP18 overexpression and knockdown were constructed. The effects of USP18 on macrophage polarization, immune function, and fatty acid β-oxidation during RSV infection were evaluated using immunofluorescence, ELISA, fatty acid oxidation (FAO) assays, boron-dipyrromethene (BODIPY) staining, and Western blot.

RESULTS

USP18 was markedly overexpressed in RSV-infected samples. USP18 knockdown in mice alleviated lung damage, reduced M2 macrophage markers, and enhanced CD8+ T cell activity. Cellular experiments demonstrated that USP18 promotes M2 macrophage polarization by enhancing fatty acid β-oxidation and regulating the expression of related enzymes, including ACLY, FASN, and ACC1. Elevated USP18 in macrophages during RSV infection inhibits CD8+ T cell activation, contributing to immune suppression. These effects were reversible with FAO inhibitors.

CONCLUSIONS

USP18 upregulation in RSV-infected cells induces M2 macrophage polarization via fatty acid β-oxidation, thereby promoting immune suppression.