Age- and Genotype-Associated Specific Expression of IL-1 and TNF Receptors on Immunocompetent Cells.

A cohort of 144 healthy donors was stratified into two age clusters using unsupervised clustering: a 'young' group (18-31 years, n=71) and an 'older' group (32-59 years, n=73).

• Unsupervised clustering methodology was used to define the age groups rather than arbitrary predefined cutoffs.
• The young group ranged from 18-31 years and the older group from 32-59 years.
• Membrane expression of TNFR1, TNFR2, IL-1R1, and IL-1R2 was analyzed on T-lymphocytes, B-lymphocytes, and monocytes by flow cytometry.
• Both percentage of receptor-positive cells and number of receptors per cell (absolute quantification with calibration beads) were measured.
• Genotyping for eight SNPs in the TNFR1, TNFR2, IL1R1, and IL1R2 genes was performed via PCR-RFLP.

The young cohort exhibited a significantly higher percentage of TNFR1- and TNFR2-positive monocytes compared to the older cohort.

• Monocytes showed the most pronounced age-related differences in receptor expression.
• The difference in TNFR1-positive and TNFR2-positive monocyte percentages was statistically significant between the young and older clusters.
• The observed receptor downregulation in older adults is described as likely reflecting an active process of ligand-induced desensitization driven by chronic inflammation.
• These findings were specific to monocytes, with less pronounced patterns in other cell types for these receptors.

The young cohort exhibited a higher number of IL-1R1 receptors per cell on monocytes compared to the older cohort.

• Absolute quantification using calibration beads was used to determine the number of receptors per cell.
• This age-related difference in IL-1R1 receptor density was observed specifically in monocytes.
• The finding indicates that monocytes from younger individuals have greater IL-1R1 surface density.
• This was part of a broader pattern of monocyte receptor downregulation with aging.

T-lymphocytes from the older cluster showed a higher percentage of TNFR2-positive cells compared to the young cluster.

• This finding was directionally opposite to the pattern observed in monocytes, where young donors had higher receptor expression.
• The age-related increase in TNFR2-positive T-lymphocytes in the older group represents a cell-type-specific pattern of receptor expression change.
• This differential pattern across cell types highlights that aging does not uniformly downregulate cytokine receptor expression across all immune cell populations.

Genetic polymorphisms modulated receptor expression in an age-dependent and cell-type-specific manner.

• In the young cluster, polymorphisms primarily affected receptor levels on B-lymphocytes.
• In the older cluster, the most significant genotype-receptor associations were observed in monocytes.
• Eight SNPs in the TNFR1, TNFR2, IL1R1, and IL1R2 genes were analyzed.
• The age-dependent effect of genetic polymorphisms demonstrates a dynamic interplay between genetics and immunosenescence.

Monocytes were identified as the immune cell population most significantly affected by age-related changes in IL-1 and TNF receptor expression.

• Monocytes showed significant age-related differences in TNFR1-positive percentage, TNFR2-positive percentage, and IL-1R1 receptor number.
• In the older cluster, monocytes were also the primary cell type showing significant genotype-receptor associations.
• The authors interpret receptor downregulation in older monocytes as likely reflecting ligand-induced desensitization driven by chronic inflammation (inflammaging).
• The cell-specificity of these findings underscores that inflammaging has differential impacts on distinct immune cell populations.

Aging is associated with 'inflammaging,' a chronic low-grade inflammatory state driven by dysregulated signaling of pro-inflammatory cytokines including IL-1 and TNF-α.

• The biological impact of IL-1 and TNF-α is modulated by the expression of their cellular receptors.
• Receptor expression is influenced by genetic polymorphisms.
• The interplay between age, genetic variation, and cell-type-specific receptor expression was described as incompletely characterized prior to this study.
• The study was motivated by the need to characterize how aging and genetics jointly regulate cytokine receptor landscapes on immunocompetent cells.