Cell surface CD11c as a neutrophil aging marker molecule.

Neutrophils exhibit substantial functional heterogeneity shaped by both developmental stage and cellular maturation, but their mechanisms remain incompletely defined. CD11c (ITGAX) is traditionally considered as a cell surface marker of dendritic cells. We recently reported that it is highly expressed intracellularly in neutrophils and contributes to their maturation; however, its role at the cell surface is unclear. Here, we showed that surface CD11c expression level was heterogeneous across neutrophils, enabling classification into CD11chi and CD11c-/lo populations. CD11chi neutrophils display enhanced phagocytic capacity and features of neutrophil aging, including increased CXCR4 and reduced CD62L expression. Bulk RNA sequencing across the three pediatric age groups revealed that differentially expressed genes (DEGs) between CD11chi and CD11c-/lo neutrophils were observed most in infants followed by preschool age children. Infant neutrophils exhibited reduced phagocytic capacity and distinct gene expression patterns compared to older children. Functional interrogation of candidate genes (ANXA2, COL6A3, DCN) demonstrated their role in regulating phagocytosis without affecting reactive oxygen species production. Machine learning analysis further identified age-dependent ontology of the DEGs associated with cell surface CD11c expression, including pathways related to adhesion, extracellular matrix interactions, stress responses, and metabolic regulation. Integrative network analysis positioned CD11c linked to cytoskeletal remodeling and phagocytosis. Collectively, these findings support a model in which developmental age establishes the baseline transcriptional landscape of neutrophils, while CD11c serves as a marker of neutrophil aging rather than acting as a primary driver of transcriptional reprogramming.