Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
Year: 2017
Type: article
Abstract: Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid-inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor-associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I-induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV.
Source: Science Signaling
Institutions: Yale University, Howard Hughes Medical Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Awards: G1485509030, G1660974751, G1991406835, G2143840936, G2770709741, G2949079525, Midcareer Award in Translational Immunology of Aging, G64361101, G6456789961, G649443540, G6665377110, Predoctoral Training Program in Virology, Interdisciplinary Immunology Training Program, Immune signatures of vaccine responses in vulnerable populations, Claude D. Pepper Older Americans Independence Center at Yale
OpenAlex ID: W2773620555