Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta)

Abstract

Aged individuals are more susceptible to infections due to a general decline in immune function broadly referred to as immune senescence. While age-related changes in the adaptive immune system are well documented, aging of the innate immune system remains less well understood, particularly in nonhuman primates. A more robust understanding of age-related changes in innate immune function would provide mechanistic insight into the increased susceptibility of the elderly to infection. Rhesus macaques have proved a critical translational model for aging research, and present a unique opportunity to dissect age-dependent modulation of the innate immune system. We examined age-related changes in: (i) innate immune cell frequencies; (ii) expression of pattern recognition receptors (PRRs) and innate signaling molecules; (iii) cytokine responses of monocytes and dendritic cells (DC) following stimulation with PRR agonists; and (iv) plasma cytokine levels in this model. We found marked changes in both the phenotype and function of innate immune cells. This included an age-associated increased frequency of myeloid DC (mDC). Moreover, we found toll-like receptor (TLR) agonists lipopolysaccharide (TLR4), fibroblast stimulating ligand-1 (TLR2/6), and ODN2006 (TLR7/9) induced reduced cytokine responses in aged mDC. Interestingly, with the exception of the monocyte-derived TNFα response to LPS, which increased with age, TNFα, IL-6, and IFNα responses declined with age. We also found that TLR4, TLR5, and innate negative regulator, sterile alpha and TIR motif containing protein (SARM), were all expressed at lower levels in young animals. By contrast, absent in melanoma 2 and retinoic acid-inducible gene I expression was lowest in aged animals. Together, these observations indicate that several parameters of innate immunity are significantly modulated by age and contribute to differential immune function in aged macaques.

Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques

“…For IL-8, middle-aged monkeys averaged 242 ± 179 pg/mL, which was significantly lower than for all of the old monkeys (data not shown). These serum IL-8 values are comparable to other recent reports of adult macaques (Asquith et al 2012). IL-10 in the middle-aged monkeys (mean, 3.03±5.06 pg/mL) did not differ from the older monkeys in either diet condition.…”

“…These nutritional effects on cytokine concentrations were not due to CR-induced reductions in age-related morbidity or visceral fat (Colman et al 2009). The occurrence of such high IL-8 values in the aged monkeys was unexpected, but the range determined for middle-aged monkeys was comparable to a recent report (Asquith et al 2012), suggesting that the IL-8 was accurately determined.…”

“…Aged healthy participants older than 60 years have higher circulating IL-8 relative to participants aged 30-60 years (AlvarezRodríguez et al 2012). In a recent report that examined the cytokine profile of aged rhesus monkeys (Asquith et al 2012), there was a similar but nonsignificant trend for higher IL-8 in aged versus adult macaques. IL-8 is also more highly expressed in mild cognitive impairment and Alzheimer's dementia (Galimberti et al 2003(Galimberti et al , 2006.…”

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

“…During immune reconstitution the ratios of naive, EM and CM shift, resulting in the EM population dominating the CD8 T cell compartment and CM population dominating the CD4 T cell compartment. These changes are similar to those observed with ageing in RM, where EM T cells relatively outnumber the naive and CM T cells within the CD8 subset while CM T cells are the dominant memory population in the CD4 subset [84]. These changes are probably the result of increased levels of homeostatic proliferation [61,85].…”

Limited susceptibility of rhesus macaques to a cowpox virus isolated from a lethal outbreak among New World monkeys

“…The 2003 outbreak in the USA caused by prairie dogs infected by imported exotic pets from Africa clearly showed that monkeypox is not restricted to Africa and can be transmitted at any time to any place (Centers for Disease, C. a. P., 2003;Reed et al, 2004). So far, no licensed antiviral treatment for poxvirus infections is available.…”