Siglec-1 upregulation and macrophage activation in age-related hearing loss: insights from integrated transcriptomic studies in mice and humans.

Abstract

Macrophage activation is closely associated with age-related hearing loss (ARHL), and Siglec-1 may be involved in modulating macrophage activation. This study aimed to investigate the immunological mechanisms underlying spiral ganglion neuron (SGN) degeneration in ARHL, with a focus on the roles of the immune regulatory gene Siglec-1 and immune regulatory cells, macrophages. Combined transcriptomic sequencing of SGNs from ARHL mice and peripheral blood samples from ARHL patients identified significant upregulation of Siglec-1 in aged groups. Auditory brainstem response (ABR) testing and histological analysis confirmed that hearing thresholds increased and SGN density decreased significantly with age, exhibiting a strong negative correlation. Subsequently, both immunofluorescence and Western blot analyses revealed a notable upregulation of Siglec-1 expression within the spiral ganglion of aged mice. Further RT-PCR analysis revealed that the expression levels of both pro-inflammatory cytokines (including IL-6, TNF-α, and IFN-γ) and the anti-inflammatory cytokine IL-10 were significantly elevated in the aging spiral ganglion tissue. Meanwhile, notable macrophage activation was observed within the spiral ganglion, particularly involving M1 pro-inflammatory macrophages. These findings suggest that Siglec-1 may play a role in the inflammatory response. Finally, we also confirmed a positive correlation between Siglec-1 mRNA expression in human blood samples with age and severity of hearing loss. These findings suggest that Siglec-1 may promote SGN degeneration in ARHL by modulating macrophage-mediated neuroinflammation and represents a potential blood immune biomarker and therapeutic target.