J Leukoc Biol. 2026 Jan 19:qiag011. doi: 10.1093/jleuko/qiag011. Online ahead of print.

ABSTRACT

Age-related decline in neutrophil function reduces vaccine protection against Streptococcus pneumoniae. In vaccinated hosts, neutrophil activation via complement and Fcγ receptors mediates bacterial uptake and killing. Mechanisms behind age-related changes in signaling of these receptors is unknown. Using neutrophils from young and old mice, we found opsonin-dependent differences in MAPK activation. Neutrophils from old mice had higher basal phosphorylation of MAPK proteins compared to young controls, including a 15-fold increase in phosphorylated ERK1/2, but failed to increase phosphorylation upon infection with antibody-opsonized bacteria. Inhibition of ERK1/2 signaling blunted killing of antibody-opsonized pneumococci by neutrophils from young mice but improved killing in old mice. In young adult human participants, inhibition of ERK1/2 signaling in neutrophils decreased pneumococcal killing, but only in vaccinated hosts, demonstrating the clinical relevance of this pathway. This study demonstrates that balanced activation of ERK1/2 is crucial for neutrophil antimicrobial activity against antibody-opsonized bacteria but is disrupted in old hosts.

PMID:41549468 | DOI:10.1093/jleuko/qiag011