Crosstalk between circadian rhythmicity, mitochondrial dynamics and macrophage bactericidal activity

Abstract

SummaryBiological functions show rhythmic fluctuations with 24-hr periodicity regulated by circadian proteins encoded by the so-called 'clock' genes. The absence or deregulation of circadian proteins in mice leads to metabolic disorders and in vitro models have shown that the synthesis of proinflammatory cytokines by macrophages follows a circadian rhythm so showing a link between circadian rhythmicity, metabolism and immunity. Recent evidence reveals that mitochondrial shape, position and size, collectively referred to as mitochondrial dynamics, are related to both cell metabolism and immune function. However, studies addressing the simultaneous crosstalk between circadian rhythm, mitochondrial dynamics and cell immune function are scarce. Here, by using an in vitro model of synchronized murine peritoneal macrophages, we present evidence that the mitochondrial dynamics and the mitochondrial membrane potential (Δw m ) follow a circadian rhythmic pattern. In addition, it is shown that the fusion of mitochondria along with high Δw m , indicative of high mitochondrial activity, precede the highest phagocytic and bactericidal activity of macrophages on Salmonella typhimurium. Taken together, our results suggest a timely coordination between circadian rhythmicity, mitochondrial dynamics, and the bactericidal capacity of macrophages.

The Circadian Nature of Mitochondrial Biology

“…Mitochondria in macrophages exhibit daily morphological changes in vitro as well (29). By contrast, the overall number of mitochondria, assessed by mitochondrial genome copy number, appears to be constant throughout the day and is independent of clock genes (16, 17, 20, 30).…”

Immunometabolism: Is it under the eye of the clock?

“…Macrophage phagocytosis is also heightened at the transition into the active phase in mice [66]. Using the serum shock model, a cell culture technique to synchronise clocks in vitro [67], circadian rhythms in phagocytosis of S. typhimurium and bactericidal activity were observed [68]. Bacterial uptake and killing in murine macrophages was greatest at 16 hr post serum shock.…”

“…This study implicates a major role for Bmal1 and the molecular clock in mitochondrial function, energy metabolism and mitochondrial ROS. Circadian variations in mitochondrial function have been demonstrated in immune cells [68]. Synchronized murine peritoneal macrophages at the beginning of serum shock exhibit fragmented, fissioned mitochondria, whereas 12-16 hrs post serum shock the mitochondria had undergone fusion forming mitochondrial networks.…”

Daily variation in macrophage phagocytosis is clock‐independent and dispensable for cytokine production

“…The capability of immune cells to internalize inflammogenic material has also been studied in the context of circadian biology . Daily oscillations in the capacity of peritoneal cells to phagocytose Zymosan and clock regulation of Streptococcus pneumoniae and Serratia marcescens phagocytosis in Drosophila among others were described.…”

“…The capability of immune cells to internalize inflammogenic material has also been studied in the context of circadian biology. [27][28][29] Daily oscillations in the capacity of peritoneal cells to phagocytose Zymosan 27 and clock regulation of Streptococcus pneumoniae and Serratia marcescens phagocytosis in Drosophila 28 among others were described. Further, melatonin, a hormone primarily produced by the pineal gland under the control of the suprachiasmatic nucleus, which projects lighting information to tissues throughout the body, has been identified as a potent regulator of particle ingestion in a variety of cell types.…”