Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells
The development of chronic inflammation, called inflammaging, contributes to the pathogenesis of age-related diseases. Although it is known that both B and T lymphocyte compartments of the adaptive immune system deteriorate with advancing age, the impact of aging on immune functions of Th17-type CD161-expressing innate immune cells and their role in inflammaging remain incompletely understood. Here, utilizing the nonhuman primate model of rhesus macaques, we report that a dysregulated Th17-type effector function of CD161+ immune cells is associated with leaky gut and inflammatory phenotype of aging. Higher plasma levels of inflammatory cytokines IL-6, TNF-α, IL-1β, GM-CSF, IL-12, and Eotaxin correlated with elevated markers of gut permeability including LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and sCD14 in aging macaques. Further, older macaques displayed significantly lower frequencies of circulating Th17-type immune cells comprised of CD161+ T cell subsets, NK cells, and innate lymphoid cells. Corresponding with the increased markers of gut permeability, production of the type-17 cytokines IL-17 and IL-22 was impaired in CD161+ T cell subsets and NK cells, along with a skewing towards IFN-γ cytokine production. These findings suggest that reduced frequencies of CD161+ immune cells along with a specific loss in Th17-type effector functions contribute to impaired gut barrier integrity and systemic inflammation in aging macaques. Modulating type-17 immune cell functions via cytokine therapy or dietary interventions towards reducing chronic inflammation in inflammaging individuals may have the potential to prevent or delay age-related chronic diseases and improve immune responses in the elderly population.
KeywordsInflammaging Leaky gut CD161+ cells I-FABP LBP sCD14
The authors acknowledge Mary Barnes and Melissa Pattison of the Pathogen Detection and Quantification Core of Tulane National Primate Research Center (TNPRC) for assistance with the multiplex cytokine detection assays and use of the Bioplex-200 instrumentation, and the clinical veterinary staff in the Division of Veterinary Medicine at TNPRC for coordinating the blood collections. Technical assistance of the flow cytometry core facility staff at the TNPRC is greatly appreciated.
Namita Rout was responsible for the study design, data analysis and interpretation and wrote the manuscript. Edith Walker coordinated the overall work including sample collection procedures and conducting the flow cytometry data analysis and in vitro functional assays and helped with manuscript preparation. Nadia Slisarenko and Giovanni Gerrets helped with sample collection and processing and data analysis. Elizabeth S. Didier and Marcelo J. Kuroda provided samples and contributed to the study design. Patricia Kissinger performed the statistical data analyses. Ronald S. Veazey and S. Michal Jazwinski helped with overall data interpretation. All authors read and approved the final manuscript. All authors helped edit and reviewed the final manuscript.
This study was supported by the National Institute of General Medical Sciences grant P20 GM103629, as well as the National Institutes of Health (NIH) base grant for TNPRC OD011104-54. The support of NIH grants U42 OD010568 and U42 OD024282 for the macaque breeding colony at TNPRC and additional support from the NIH grants AI097059, AG052349, HL139278 funded studies is acknowledged.
Compliance with ethical standards
This study was performed using samples collected from nonhuman primates. All procedures were approved by the TNPRC Institutional Animal Care and Use Committee, Animal Welfare Assurance A-4499-01, and were performed in accordance with the Guide for the Care and Use of Laboratory Animals, National Research Council, 2011. The TNPRC maintains an AAALAC-I accredited animal care and use program.
Conflict of interest
The authors declare that they have no conflict of interest.
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