Light and Circadian Rhythmicity – Neutrophils
The most abundant type of circulating myeloid cell is the neutrophil, making up approximately 50–70% of all white blood cells. This type of granulocyte plays a key role against bacterial and fungal infections. Each day the bone marrow (BM) produces billions of these cells that enter the blood stream and then infiltrate the peripheral organs where ultimately they are cleared out. This massive production by the BM is needed because of the half-life of neutrophils that has been indicated to be 10 hours.
The short life predisposes neutrophils to a circadian timekeeping (1). A circadian (~24 hours) regulation implies the presence of oscillating core clock genes and of external cues to synchronize their expression with the environment. Generally speaking, one of the most potent external cue capable of synchronizing circadian cycles is light.
A recent report published in Science Immunology shows that in a model using zebrafish larvae light is able to boost the bactericidal action of neutrophils. Apparently, in this transparent fish, light can directly activate clock genes such as clock, bmal1, per, and cry in neutrophils resulting in an increased bactericidal activity. At the end of this elegant study the authors conclude:
“In summary, by using the live imaging of transparent larval zebrafish, we show that neutrophil bactericidal activity is circadian-gated, is transcriptionally controlled by the core clock components Per2 and Cry1a, and functions to boost host protection during the active phase. Our work provides fundamental mechanistic insights into the transcriptional regulation of CCGs (circadian clock genes) in immune cells, describes an additional function for the evolutionarily conserved protein( high-mobility group box 1a) HMGB1, helps explain time- of- day variations in host antibacterial defense, and raises the possibility of targeting the neutrophil clock-work to better manage bacterial infections” (2).
Now, it is known that, in Zebrafish, all cell types are photoresponsive due to the presence of photopigments such as melanopsin (3). Thus this conclusion is undeniably valid as far as it concerns the Zebrafish organism but it cannot be directly extended to mammals for obvious reasons. Nevertheless, as the authors of the study point out, it is possible that in mammals, neutrophils also use circadian clock components to regulate intracellular antibacterial activity involving the expression of the HMGB1 protein.
As a matter of fact, it has been reported that the circadian transformations observed in circulating neutrophils in mice occur in a matter of hours before the cell is eliminated (4). Therefore, individual neutrophils are influenced by only one diurnal cycle and not by several circadian oscillations like other cell types. Furthermore, the circadian aging of neutrophils starts only when they enter the blood circulation suggesting that their internal clock is kept off while they reside in the BM.
This happens because of the high level of CXCL12 and CXCR4 signaling that occurs in the hematopoietic niche. Circadian aging that occurs after mobilization is driven by BMAL1 accumulation which regulates Cxcl2 production, and this is functionally necessary for the migration of neutrophils into peripheral tissues, for their distribution in the organism and for their physiological function (4,5). So CCGs do participate in mammalian neutrophils functions even if the specific question about the possible relation of HMGB1 production remains to be established.
Of note, and at variance with Zebrafish neutrophils, mammalian neutrophils are not directly influenced by light, instead the circadian oscillation of their function is related to the master biological clock located in the suprachiasmatic nucleus of the hypothalamus (SCN), which drives the entire circadian machinery of the organism. Blue light (around 480 nm of wavelength) is sensed by melanopsin-containing ganglionic cells located in the frontal part of the retina. The ensuing non-visual nervous signal travels in the retino-hypothalamic tract through to the SCN entraining its rhythm.
The oscillation of the SCN activity is generated by the cyclical expression of clock genes in both its neurons and astrocytes regulated by a reciprocal signaling. In particular, neurons are active during daytime while astrocytes downregulate neurons during nighttime by controlling extracellular glutamate concentration [6].
This rhythm then dictates the circadian oscillation of melatonin synthesis in the pineal gland, the daily oscillation of the sympathetic nervous system (SNS) activity as well as of the hypothalamic-pituitary-adrenal (HPA) axis. Altogether, these circadian signals entrain clock genes expression in peripheral tissues including the BM.
Reliably, either catecholamines (the end products of the SNS), or melatonin and corticosteroids, do participate in the regulation of the hematopoietic niche (7). In particular, the circadian oscillation of catecholamines production by the varicosities of the sympathetic nerve terminals in the hematopoietic niche regulates the migration of hematopoietic stem cells and mature leukocytes in and out the BM. This happens because of a beta-adrenergic regulation of the expression of CXCL12 by a type of mesenchymal cells called CXCL12-abundant reticular cells (CAR cells).
The current opinion about the physiological relevance of the circadian regulation of hematopoietic stem/progenitor cells and mature leukocytes circulation as well as of their homing in the BM or peripheral tissues, claims that such trafficking is necessary to maintain an efficient hematopoietic niche as well as to patrol the organism to ensure the appropriate response in case of infection (7).
Neutrophil mobilization occurs during the resting phase of the circadian cycle in both diurnal and nocturnal mammals while tissue homing happens in the active phase when the probability to encounter an infectious agent is higher. Thus, in mammals, the effect of light on neutrophil function seems to be fundamentally mediated by its entraining action on the SCN and the consequent circadian regulation of the neural and hormonal factors influencing hematopoiesis.
Commentary
On L. Du, Pramuk Keerthisinghe et al. A light-regulated circadian timer optimizes neutrophil bactericidal activity to boost daytime immunity, May 2025, Science Immunology 10(107), DOI:10.1126/sciimmunol.adn3080
Author’s Affiliation
Georges JM Maestroni – Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy. georges.maestroni@tim.it
References
- Ovadia S, Özcan A, Hidalgo A. The circadian neutrophil, inside-out.J Leukoc Biol. 2023;113(6):555-566. doi:10.1093/jleuko/qiad038
- Du LY, Keerthisinghe P, Rolland L, et al. A light-regulated circadian timer optimizes neutrophil bactericidal activity to boost daytime immunity. Sci Immunol. 2025;10(107):eadn3080. doi:10.1126/sciimmunol.adn3080
- Ramos BC, Moraes MN, Poletini MO, Lima LH, Castrucci AM. From blue light to clock genes in zebrafish ZEM-2S cells.PLoS One. 2014;9(9):e106252. Published 2014 Sep 3. doi:10.1371/journal.pone.0106252
- Adrover JM, Del Fresno C, Crainiciuc G, et al. A Neutrophil Timer Coordinates Immune Defense and Vascular Protection.Immunity. 2019;50(2):390-402.e10. doi:10.1016/j.immuni.2019.01.002
- Adrover JM, Aroca-Crevillén A, Crainiciuc G, et al. Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation. Nat Immunol. 2020;21(2):135-144. doi:10.1038/s41590-019-0571-2
- Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling. 2017 Mar 22;93(6):1420-1435.e5. doi: 10.1016/j.neuron.2017.02.030. Epub 2017 Mar 9. PMID: 28285822; PMCID: PMC5376383.
- Maestroni G. The Sympathetic Nervous Influence on Hematopoiesis Up To Date. J Neuroimmune Pharmacol. 2025;20(1):61. Published 2025 May 30. doi:10.1007/s11481-025-10220-7
Cover Image Credit (left panel): Circadian rhythm (with labels), from: https://nigms.nih.gov/image-gallery/2569; ID: 2569; The human body keeps time with a master clock called the suprachiasmatic nucleus or SCN. Situated inside the brain, it’s a tiny sliver of tissue about the size of a grain of rice, located behind the eyes. It sits quite close to the optic nerve, which controls vision, and this means that the SCN “clock” can keep track of day and night.
The SCN helps control sleep and maintains our circadian rhythm–the regular, 24-hour (or so) cycle of ups and downs in our bodily processes such as hormone levels, blood pressure, and sleepiness. The SCN regulates our circadian rhythm by coordinating the actions of billions of miniature “clocks” throughout the body. These aren’t actually clocks, but rather are ensembles of genes inside clusters of cells that switch on and off in a regular, 24-hour (or so) cycle in our physiological day; Source: Crabtree + Company
Related stories you may like:
Alpha-Adrenergic Receptors And Hematopoiesis
Stress and Hematopoiesis: Activation of Hematopoietic stem cells and Neutrophil and Monocyte Production
Circadian oscillations in leukocyte migration and their control by sympathetic nerves
Autonomic Nervous System Control of Leukocyte Distribution: Physiology and Implications
Sympathetic Nerves via β2-adrenoceptor Signaling Generate Circadian Rhythms and Govern Lymphocyte Recirculation in Lymph Nodes
Tachykinins, Bone Marrow and Hematopoiesis
The Connection Between Light and Circadian Rhythmicity of Neutrophil Bactericidal Activity: Possible Mechanisms
Light and Circadian Rhythmicity – Neutrophils
The most abundant type of circulating myeloid cell is the neutrophil, making up approximately 50–70% of all white blood cells. This type of granulocyte plays a key role against bacterial and fungal infections. Each day the bone marrow (BM) produces billions of these cells that enter the blood stream and then infiltrate the peripheral organs where ultimately they are cleared out. This massive production by the BM is needed because of the half-life of neutrophils that has been indicated to be 10 hours.
The short life predisposes neutrophils to a circadian timekeeping (1). A circadian (~24 hours) regulation implies the presence of oscillating core clock genes and of external cues to synchronize their expression with the environment. Generally speaking, one of the most potent external cue capable of synchronizing circadian cycles is light.
A recent report published in Science Immunology shows that in a model using zebrafish larvae light is able to boost the bactericidal action of neutrophils. Apparently, in this transparent fish, light can directly activate clock genes such as clock, bmal1, per, and cry in neutrophils resulting in an increased bactericidal activity. At the end of this elegant study the authors conclude:
“In summary, by using the live imaging of transparent larval zebrafish, we show that neutrophil bactericidal activity is circadian-gated, is transcriptionally controlled by the core clock components Per2 and Cry1a, and functions to boost host protection during the active phase. Our work provides fundamental mechanistic insights into the transcriptional regulation of CCGs (circadian clock genes) in immune cells, describes an additional function for the evolutionarily conserved protein( high-mobility group box 1a) HMGB1, helps explain time- of- day variations in host antibacterial defense, and raises the possibility of targeting the neutrophil clock-work to better manage bacterial infections” (2).
Now, it is known that, in Zebrafish, all cell types are photoresponsive due to the presence of photopigments such as melanopsin (3). Thus this conclusion is undeniably valid as far as it concerns the Zebrafish organism but it cannot be directly extended to mammals for obvious reasons. Nevertheless, as the authors of the study point out, it is possible that in mammals, neutrophils also use circadian clock components to regulate intracellular antibacterial activity involving the expression of the HMGB1 protein.
As a matter of fact, it has been reported that the circadian transformations observed in circulating neutrophils in mice occur in a matter of hours before the cell is eliminated (4). Therefore, individual neutrophils are influenced by only one diurnal cycle and not by several circadian oscillations like other cell types. Furthermore, the circadian aging of neutrophils starts only when they enter the blood circulation suggesting that their internal clock is kept off while they reside in the BM.
This happens because of the high level of CXCL12 and CXCR4 signaling that occurs in the hematopoietic niche. Circadian aging that occurs after mobilization is driven by BMAL1 accumulation which regulates Cxcl2 production, and this is functionally necessary for the migration of neutrophils into peripheral tissues, for their distribution in the organism and for their physiological function (4,5). So CCGs do participate in mammalian neutrophils functions even if the specific question about the possible relation of HMGB1 production remains to be established.
Of note, and at variance with Zebrafish neutrophils, mammalian neutrophils are not directly influenced by light, instead the circadian oscillation of their function is related to the master biological clock located in the suprachiasmatic nucleus of the hypothalamus (SCN), which drives the entire circadian machinery of the organism. Blue light (around 480 nm of wavelength) is sensed by melanopsin-containing ganglionic cells located in the frontal part of the retina. The ensuing non-visual nervous signal travels in the retino-hypothalamic tract through to the SCN entraining its rhythm.
The oscillation of the SCN activity is generated by the cyclical expression of clock genes in both its neurons and astrocytes regulated by a reciprocal signaling. In particular, neurons are active during daytime while astrocytes downregulate neurons during nighttime by controlling extracellular glutamate concentration [6].
This rhythm then dictates the circadian oscillation of melatonin synthesis in the pineal gland, the daily oscillation of the sympathetic nervous system (SNS) activity as well as of the hypothalamic-pituitary-adrenal (HPA) axis. Altogether, these circadian signals entrain clock genes expression in peripheral tissues including the BM.
Reliably, either catecholamines (the end products of the SNS), or melatonin and corticosteroids, do participate in the regulation of the hematopoietic niche (7). In particular, the circadian oscillation of catecholamines production by the varicosities of the sympathetic nerve terminals in the hematopoietic niche regulates the migration of hematopoietic stem cells and mature leukocytes in and out the BM. This happens because of a beta-adrenergic regulation of the expression of CXCL12 by a type of mesenchymal cells called CXCL12-abundant reticular cells (CAR cells).
The current opinion about the physiological relevance of the circadian regulation of hematopoietic stem/progenitor cells and mature leukocytes circulation as well as of their homing in the BM or peripheral tissues, claims that such trafficking is necessary to maintain an efficient hematopoietic niche as well as to patrol the organism to ensure the appropriate response in case of infection (7).
Neutrophil mobilization occurs during the resting phase of the circadian cycle in both diurnal and nocturnal mammals while tissue homing happens in the active phase when the probability to encounter an infectious agent is higher. Thus, in mammals, the effect of light on neutrophil function seems to be fundamentally mediated by its entraining action on the SCN and the consequent circadian regulation of the neural and hormonal factors influencing hematopoiesis.
Commentary
On L. Du, Pramuk Keerthisinghe et al. A light-regulated circadian timer optimizes neutrophil bactericidal activity to boost daytime immunity, May 2025, Science Immunology 10(107), DOI:10.1126/sciimmunol.adn3080
Author’s Affiliation
Georges JM Maestroni – Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy. georges.maestroni@tim.it
References
Cover Image Credit (left panel): Circadian rhythm (with labels), from: https://nigms.nih.gov/image-gallery/2569; ID: 2569; The human body keeps time with a master clock called the suprachiasmatic nucleus or SCN. Situated inside the brain, it’s a tiny sliver of tissue about the size of a grain of rice, located behind the eyes. It sits quite close to the optic nerve, which controls vision, and this means that the SCN “clock” can keep track of day and night.
The SCN helps control sleep and maintains our circadian rhythm–the regular, 24-hour (or so) cycle of ups and downs in our bodily processes such as hormone levels, blood pressure, and sleepiness. The SCN regulates our circadian rhythm by coordinating the actions of billions of miniature “clocks” throughout the body. These aren’t actually clocks, but rather are ensembles of genes inside clusters of cells that switch on and off in a regular, 24-hour (or so) cycle in our physiological day; Source: Crabtree + Company
Related stories you may like:
Alpha-Adrenergic Receptors And Hematopoiesis
Stress and Hematopoiesis: Activation of Hematopoietic stem cells and Neutrophil and Monocyte Production
Circadian oscillations in leukocyte migration and their control by sympathetic nerves
Autonomic Nervous System Control of Leukocyte Distribution: Physiology and Implications
Sympathetic Nerves via β2-adrenoceptor Signaling Generate Circadian Rhythms and Govern Lymphocyte Recirculation in Lymph Nodes
Tachykinins, Bone Marrow and Hematopoiesis