SLAMF7-mediated macrophage polarization dysregulation: A novel mechanism in pneumonia

Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Despite advances in antibiotic therapy, treatment outcomes remain suboptimal due to increased pathogen resistance and dysregulated host immune responses. Macrophage polarization plays a crucial role in pulmonary inflammation, and its dysregulation can lead to uncontrolled inflammatory responses. Although SLAM family member 7 (SLAMF7) is recognized as an important immunomodulatory molecule in various immune diseases, its role and molecular mechanism in bacterial pneumonia remain unclear.

We established a bacterial pneumonia mouse model and specifically suppressed SLAMF7 expression via adeno-associated virus-mediated gene silencing. Macrophage polarization was analyzed by flow cytometry, inflammatory cytokine levels were measured by ELISA, and pathological changes in lung tissue were evaluated by Hematoxylin and Eosin (H&E) staining. Primary alveolar macrophages were isolated and cultured in vitro to examine SLAMF7 expression and its effects on macrophage polarization by western blotting, qRT-PCR, and immunofluorescence staining. The Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway was specifically blocked using small-molecule inhibitors to verify its role in SLAMF7-mediated macrophage polarization. Statistical analysis was performed using SPSS software, with statistical significance set at P < 0.05.

SLAMF7 expression was significantly upregulated in the bacterial pneumonia model. SLAMF7 knockout attenuates bacteria-induced lung injury and improves survival in mice Silencing SLAMF7 significantly inhibited pulmonary macrophage polarization toward the pro-inflammatory M1 phenotype. Mechanistic studies revealed that SLAMF7 promoted M1 polarization while suppressing M2 polarization through the activation of the NF-κB signaling pathway. In vitro experiments confirmed that SLAMF7 specifically induces M1 polarization without affecting macrophage proliferation and migration. NF-κB inhibition reverses SLAMF7-induced M1 macrophage polarization. In vivo, blocking the NF-κB signaling pathway significantly ameliorated the SLAMF7-mediated exacerbation of pneumonia.

This study revealed a novel SLAMF7-NF-κB-macrophage polarization axis in bacterial pneumonia and demonstrated that SLAMF7 promotes M1 macrophage polarization through NF-κB pathway activation, thereby exacerbating pulmonary inflammation. These findings not only expand our understanding of immune cell polarization regulatory mechanisms but also provide a theoretical basis for developing novel immunotherapeutic strategies targeting SLAMF7. Future studies should explore the upstream regulatory mechanisms of SLAMF7 and evaluate the clinical potential of SLAMF7-targeted therapeutic strategies.