Age-related changes of FCGR3A+ natural killer cells and their association with elderly atopic dermatitis

Background The increasing global ageing population has led to a rising prevalence of elderly atopic dermatitis (eAD). Natural killer (NK) cells play an important role in skin homoeostasis; however, their involvement in eAD remains unclear. This study investigates the functional role and mechanisms of NK cells in eAD pathogenesis. Methods Using single-cell RNA sequencing (scRNA-seq) complemented by flow cytometry and immunofluorescence, we identified distinct NK cell subsets in eAD lesions. In vivo functional studies were performed in an MC903-induced AD mouse model through NK cell depletion and adoptive transfer experiments. Fibroblast-NK cell-macrophage interactions were further examined using in vitro co-culture systems. Findings Our results showed that activated NK cells were increased in skin lesions of younger patients with AD. Depletion of NK cell exacerbated skin inflammation in AD mice, whereas adoptive transfer of activated NK cells alleviated it. Notably, patients with eAD exhibited a significant reduction in both NK cell number and function compared to younger patients with AD. scRNA-seq analysis identified three distinct subsets of NK cells in the skin: NK1a ( CLNK + AREG + ), NK1b ( IL12RB2 + AREG + ), and NK2 ( FCGR3A + ). The NK2 subset was reduced significantly in eAD lesions. Adoptive transfer of NK2 cells mitigated AD-like dermatitis in aged mice. Mechanistically, senescent fibroblasts impaired the recruitment of NK2 cells by disrupting the balance between CXCL14 and CXCL12 chemokine signalling. Furthermore, NK2 cells inhibited M2 macrophage polarisation, suggesting their regulatory role in skin inflammation. Interpretation In conclusion, NK cells, especially the NK2 subset, are associated with AD pathogenesis, with potential implications for elderly patients. Funding This work was funded by the National Key R&D Program of China (2022YFC3601800); National Natural Science Foundation of China (82373489, 82504273, 82530099, 82522075, 82330098, 82273542, 82304023, 82404151); CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1–059); Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC320-001); Key Project of the Innovation Program of Shanghai Municipal Education Commission (2021-01-07-00-07-E00078).