Scientist Science & Technology Ctr, HIll's Pet Nutrition Topeka, KS, United States
Abstract:
Background: Chronic age-related inflammation is a common risk factor for developing inflammatory conditions. Functional immunity declines with age causing immunosenescence. However, aging is also characterized by increased low-grade innate immune activation contributing to inflamm-aging.Hypothesis: Increased expression of pro-inflammatory cytokines and chemokines contribute to inflamm-aging in older canines.Animals: Healthy canines housed in Hill’s animal colony and divided into two groups: young (n = 17, 2-4 yr) and old (n = 15, 10-13 yr).
Methods: Total circulating RNA was used to assess gene expression using NanoString nCounter® platform and analyzed using the nSolver software.
Results: When comparing older canines to young dogs, there was significant up-regulation in CCL5, CCL4, CCR5, IL-15, TNF, NF-κB1 (p105), NF-κB2 (p100), IKBKε, Akt1, JAK3, STAT1 ( p < 0.05), and a non-significant increase in CCL3 and CD40LG. Conclusions and clinical importance: CCL4 and CCL3 are known to form dimers or larger aggregates with CCL5 in inflammatory conditions. CCR5 is a receptor for CCL3, CCL4, and CCL5. Il-15 and CD40 contribute to CCL5 production. The CCL5/CCR5 axis is hypothesized to augment vascular dysfunction in aging. CCR5/CCL5 and TNF-alpha are known to activate the NF-kB pathway. CCL5 also activates JAK3 in T-cells and NK-cells, and JAK3 subsequently activates multiple pathways including the PI3/Akt and JAK/STAT. Our results indicate importance of the CCL5/CCR5 axis in aging through activation of multiple downstream signaling pathways. Down-regulation of the CCL5/CCR5 axis through nutrition may be an attractive therapeutic strategy to attenuate immune-mediated inflammation in aging dogs.
