Sex-dependent effect of aging on calcium signaling and expression of TRPM2 and CRAC channels in human neutrophils

The vulnerability of older adults to bacterial infections has been associated with age-related changes in neutrophils. We analyzed the consequences of aging on calcium (Ca²⁺) mobilization and TRPM2 and CRAC channels expression in human neutrophils. The percentages of granulocytes, mature neutrophils, and neutrophil precursors were equivalent between young and older adults. However, neutrophil chemotaxis towards IL-8, C5a, or fMLP was lower in older adults of both sexes. Interestingly, a stronger Ca²⁺ transient followed by an identical Ca²⁺ influx to IL-8 was observed in older adult females. In addition, the Ca²⁺ response to LPS was delayed and prolonged in neutrophils of older adult males. There was no significant difference in Ca²⁺ response to fMLP, C5a, or store-operated Ca²⁺ entry in the older adults. There were also no differences in the expression of CXCR2, CD88, FPLR1, and TLR4. Interestingly, TRPM2- and ORAI1-mRNA expression was lower in neutrophils of older adults, mainly in females. Both channels were detected intracellularly in the neutrophils. TRPM2 was in late endosomes in young adults and in lysosomes in older adult neutrophils. In summary, defective neutrophil chemotaxis in aging seemed not to stem from alterations in Ca²⁺ signals; nevertheless, the low TRPM2 and ORAI1 expression may affect other functions.