Chronic inflammation is a feature of aging; the immune system is persistently overactive, and this disrupts tissue function in numerous ways, contributing to the progression of age-related disease. There are still anti-inflammatory mechanisms operating in old people, but these mechanisms are washed out by excessive pro-inflammatory signaling, the response to an age-damaged environment. Scientists here identify one such anti-inflammatory mechanism, an increased presence of microRNA-192 (miR-192) in the extracellular vesicles that pass between cells. Research of this nature may offer a basis for interventions that dial back age-related inflammation with fewer side-effects, in this case via upregulation of miR-192, an important goal in the treatment of aging.
A hyperinflammatory state has been observed in elderly humans and animals, wherein levels of IL-6 and several other pro-inflammatory cytokines in the blood are elevated. Inflammation itself is a necessary part of immune cell-mediated host protection, with pro-inflammatory cytokines mainly produced by innate immune cells, including macrophages, which are essential components for counteracting viral infections before the development of acquired immunity. However, the onset and termination of inflammatory responses must be tightly regulated because excessive inflammation or unbalanced production of inflammatory cytokines and chemokines can be detrimental to the organism.
Recent studies have revealed that small extracellular vesicles (EVs) mediate intercellular communications and influence our immune system. Aging and senescence have been found to modulate EV function, but it remains unclear whether aging affects EV-mediated immune regulation. EVs consisting of 30- to 150-nm lipid bilayer vesicles are the potent systemically circulating factors that regulate immune responses, including inflammation. These vesicles are secreted by many types of cells throughout the body for local or remote cell-to-cell communication, and they contain functional proteins and RNAs, such as microRNAs (miRNAs), which modulate cellular responses. Recent studies have shown that EVs deliver several immune regulatory miRNAs suited to different tasks.
This study found that the microRNA-192 (miR-192) is an aging-associated immune regulatory microRNA whose concentration was significantly increased in aged EVs due to the hyperinflammatory state of aged mice. Interestingly, EV miR-192 exhibited anti-inflammatory effects on macrophages. In our aged mouse model, aging was associated with prolonged inflammation in the lung upon stimulation with inactivated influenza whole virus particles (WVP), whereas EV miR-192 alleviated the prolonged inflammation associated with aging. The hyperinflammatory state of aged mice resulted in reduced production of specific antibodies and efficacy of vaccination with WVP; however, EV miR-192 attenuated this hyperinflammatory state and improved vaccination efficacy in aged mice. Our data indicate that aged EVs constitute a negative feedback loop that alleviates aging-associated immune dysfunction.