title: A circadian clock in macrophages controls inflammatory immune responses.
abstract: Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-alpha and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.
authors: Laboratory of Chronobiology, Institute for Medical Immunology, Charité-Universitätsmedizin, 10117 Berlin, Germany.
authors: Maren
authors: M
authors: Keller
authors: Jeannine
authors: J
authors: Mazuch
authors: Ute
authors: U
authors: Abraham
authors: Gina D
authors: GD
authors: Eom
authors: Erik D
authors: ED
authors: Herzog
authors: Hans-Dieter
authors: HD
authors: Volk
authors: Achim
authors: A
authors: Kramer
authors: Bert
authors: B
authors: Maier
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000276:immunology*; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha