AUTHOR=Escalona Emilia , Olate-Briones Alexandra , Albornoz-Muñoz Sofía , Bonacic-Doric Enzo , Rodríguez-Arriaza Francisca , Herrada Andrés A. , Escobedo Noelia 

TITLE=Neu1 deficiency and fibrotic lymph node microenvironment lead to imbalance in M1/M2 macrophage polarization

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1462853

DOI=10.3389/fimmu.2024.1462853

ISSN=1664-3224

ABSTRACT=<p>Macrophages play a pivotal role in tissue homeostasis, pathogen defense, and inflammation resolution. M1 and M2 macrophage phenotypes represent two faces in a spectrum of responses to microenvironmental changes, crucial in both physiological and pathological conditions. Neuraminidase 1 (Neu1), a lysosomal and cell surface sialidase responsible for removing terminal sialic acid residues from glycoconjugates, modulates several macrophage functions, including phagocytosis and Toll-like receptor (TLR) signaling. Current evidence suggests that Neu1 expression influences M1/M2 macrophage phenotype alterations in the context of cardiovascular diseases, indicating a potential role for Neu1 in macrophage polarization. For this reason, we investigated the impact of Neu1 deficiency on macrophage polarization <italic>in vitro</italic> and <italic>in vivo</italic>. Using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from <italic>Neu1</italic> knockout (<italic>Neu1<sup>−/−</sup></italic>) mice and wild-type (<italic>WT</italic>) littermate controls, we demonstrated that <italic>Neu1</italic>-deficient macrophages exhibit an aberrant M2-like phenotype, characterized by elevated macrophage mannose receptor 1 (MMR/CD206) expression and reduced responsiveness to M1 stimuli. This M2-like phenotype was also observed <italic>in vivo</italic> in peritoneal and splenic macrophages. However, lymph node (LN) macrophages from <italic>Neu1<sup>−/−</sup></italic> mice exhibited phenotypic alterations with reduced CD206 expression. Further analysis revealed that peripheral LNs from <italic>Neu1<sup>−/−</sup></italic> mice were highly fibrotic, with overexpression of transforming growth factor-beta 1 (TGF-β1) and hyperactivated TGF-β signaling in LN macrophages. Consistently, TGF-β1 was found to alter M1/M2 macrophage polarization <italic>in vitro</italic>. Our findings showed that <italic>Neu1</italic> deficiency prompts macrophages towards an M2 phenotype and that microenvironmental changes, particularly increased TGF-β1 in fibrotic tissues such as peripheral LNs in <italic>Neu1<sup>−/−</sup></italic> mice, further influence M1/M2 macrophage polarization, highlighting its sensitivity to the local microenvironment. Therapeutic interventions targeting Neu1 or TGF-β signaling pathways may offer the potential to regulate macrophage behavior across different diseases.</p>