Rev-erb-alpha antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice

Circadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific set of genes and that some pathways that are rhythmic in young-adult mice are non-rhythmic or time shifted in elderly mice. In particular, the circadian expression of the clock component Rev-erb-alpha and apelin/apelin receptor was altered in elderly mice. In young-adult mice, we discovered an interaction between Rev-erb-alpha and the apelinergic axis that controls host defenses against S. pneumoniae via alveolar macrophages. Pharmacological repression of Rev-erb-alpha in elderly mice resulted in greater resistance to pneumococcal infection. These data suggest the causative role of age-associated impairments in circadian rhythms on respiratory infections and have clinical relevance.

• Silva Angulo, F.
• Joseph, C. V.
• Delval, L.
• Deruyter, L.
• Heumel, S.
• Bicharel, M.
• Rodrigues, P. B.
• Sencio, V.
• Bourguignon, T.
• Machado, M. G.
• Fourcot, M.
• Delhaye, S.
• Salome-Desnoulez, S.
• Valet, P.
• Adnot, S.
• Wolowczuk, I.
• Sirard, J. C.
• Pichavant, M.
• Staels, B.
• Haas, J. T.
• Gref, R.
• Vandel, J.
• Machelart, A.
• Duez, H.
• Pourcet, B.
• Trottein, F.