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.

This paper carries supplementary material (Supplemental Table S1, Supplemental Figure S1).

• nonhuman primate
• innate immunity
• myeloid
• immune senscence
• pattern recognition recepto

Acknowledgements

We would like to thank Jose Vasquez, Spencer Chang, and Craig Kreklywich for their technical assistance, as well as the Division of Animal Resources (DAR) at the Oregon National Primate Research Center for expert animal care. We would also like to thank the Program for Aging Studies at the ONPRC especially Dr Steven Kohama. Our gratitude goes to Alfred Legasse, Miranda Fischer, and Jesse Dewane for the collection of blood and BAL samples. This work was supported by NIH R01AG037042, 5T32 A1078903-02, NIH 8P51 OD011092-53, and the Brookdale Foundation.