Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs.
Advanced age is associated with chronic low-grade inflammation (i.e. inflamm-aging) and poor macrophage function that includes a weak pro-inflammatory cytokine response to bacteria and diminished phagocytosis (i.e. age-dependent macrophage dysfunction [ADMD]). One reason for this is that ADMD is associated with poor NFκB and MAPK activation following Toll-like receptor stimulation. Herein, we tested the hypothesis that inflamm-aging induces production of A20, a cytosolic and homeostatic suppressor of the NFκB and MAPK signaling cascades that deubiquitinates (i.e. inactivates) the common upstream signaling molecule TRAF6, and this is responsible for ADMD. Western blots and immunohistochemistry comparing tissues from young, mature, and aged C57BL/6 mice indicated that A20 was strongly elevated in the lungs of aged mice but not in other tissues. Elevated A20 was also detected in alveolar macrophages (AM) from aged mice. In contrast CYLD, a second deubiquitinase that also negatively regulates the NFκB pathway was decreased with aging. Following co-incubation of AM with the bacteria Streptococcus pneumoniae, TRAF6 polyubiquitination was diminished in AM isolated from aged versus young mice. A20 production was inducible in the J774A.1 macrophage cell line and C57BL/6AM by overnight incubation with TNFα but not IL-6. Retrovirus-induced expression of A20 in J774A.1 cells resulted in their diminished production of IL-6 following exposure to S. pneumoniae but had no effect on levels of phagocytosis. Overnight incubation of AM from young mice with TNFα also resulted in a dampened IL-6 response to S. pneumoniae. Finally, dietary supplementation of aged mice with anti-inflammatory n-3 polyunsaturated fatty acids in the form of fish oil lowered lung A20 levels and enhanced resistance, including a 100-fold reduction in bacterial titers in the lungs, to experimental challenge with S. pneumoniae. We conclude that elevated A20 due to TNFα partially explains the ADMD phenotype and that ADMD is potentially reversible.
Center for Airway Inflammation, Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Cecilia A
CA
Hinojosa
Center for Airway Inflammation, Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Ramya
R
Akula Suresh Babu
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Md M
MM
Rahman
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Gabriel
G
Fernandes
Center for Airway Inflammation, Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Angela R
AR
Boyd
Center for Airway Inflammation, Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: orihuela@uthscsa.edu.
Carlos J
CJ
Orihuela
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005395:Fish Oils / Q000494:pharmacology; D007113:Immunity, Innate / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D011008:Pneumococcal Infections / Q000276:immunology / Q000517:prevention & control; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000517:prevention & control; D013296:Streptococcus pneumoniae; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005395:Fish Oils; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
Aging; Infection; Inflammation; Innate immunity; Macrophage; Pneumonia