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Stress-induced redistribution of immune cells–from barracks to boulevards to battlefields: a tale of three hormones–Curt Richter Award winner
Open accessAbstract
Background The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status.Methods Male Sprague Dawley rats were stressed (short-term restraint, 2-120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations.Results Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L⁻/⁺ neutrophils and CD62L⁻ monocytes, but decreased lymphocyte numbers with CD62L⁻/⁺ CTL and CD62L⁺ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L⁻ and CD62L⁺ cells being equally affected. Thus, naïve (CD62L⁺) vs. memory (CD62L⁻) T cells, classical (CD62L⁺) vs. non-classical (CD62L⁻) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones.Conclusion Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naïve or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function.
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“Immune responses and associated clinical signs require time to respond (40), and the lack of a sizable response in this study could indicate a response in development or a simple reduction in infection potential for these calves.”
From Effect of source and journey on physiological variables in calves transported by road and ferry between Ireland and the Netherlands (2023) · cites this paper as [40]
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“Monocytes showed a similar but delayed pattern, which was expected as monocyte count typically responds to stress and infection slower than other immune subsets (40).”
From Effect of source and journey on physiological variables in calves transported by road and ferry between Ireland and the Netherlands (2023) · cites this paper as [40]
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“an acute stressor activates an acquired immune response via mediation by catecholamines and glucocorticoids and locally produced immune mediators; and, yet, a chronic exposure to the same stressor over several weeks has the opposite effect and results in immune suppression.”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [5]
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Brod, S., Rattazzi, L., Piras, G., & D’Acquisto, F. (2014) · Immunology · doi:10.1111/imm.12341 · Cited by 91
Rooney, B. V., Bigley, A. B., LaVoy, E. C. P., Laughlin, M. S., Pedlar, C. R., & Simpson, R. J. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.06.008 · Cited by 86
“They may return to their pre-exercise location, or might migrate to areas/tissues that now require their sentinel and/or reparative action following activation of the biological stress response [17].”
BackgroundSleep-deprivation reduces NK cell number and function mediated by β-adrenergic signalling
De Lorenzo, B. H. P., de Oliveira Marchioro, L., Greco, C. R., & Suchecki, D. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.04.006 · Cited by 85
Understanding acute stress-mediated immunity in teleost fish
Guo, H., & Dixon, B. (2021) · Fish and Shellfish Immunology Reports · doi:10.1016/j.fsirep.2021.100010 · Cited by 84
The gut virome is associated with stress-induced changes in behaviour and immune responses in mice
Ritz, N. L., Draper, L. A., Bastiaanssen, T. F. S., Turkington, C. J. R., Peterson, V. L., van de Wouw, M., Vlčková, K., Fülling, C., Guzzetta, K. E., Burokas, A., et al. (2024) · Nature Microbiology · doi:10.1038/s41564-023-01564-y · Cited by 88
Walsh, C. P., Bovbjerg, D. H., & Marsland, A. L. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.013 · Cited by 87
Interplay between stress and cancer—A focus on inflammation
Vignjević, S., Milošević, M. S., Marković, D. C., & Momčilović, S. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1119095 · Cited by 95
“It is important to note that leukocytes exhibit distinct sensitivities and redistribution kinetics in response to each stress hormone, depending on the type of cell and its functional characteristics (Dhabhar et al., 2012).”
BackgroundNeuroinflammatory basis of depression: learning from experimental models
Afridi, R., & Suk, K. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.691067 · Cited by 82
Kotfis, K., Bott-Olejnik, M., Szylińska, A., & Rotter, I. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071075 · Cited by 75
“The initial response in generalized stress, including stroke, is a nonspecific activation of the immune system, where the first-line response is the increase in neutrophil count and a decrease in the lymphocyte count [32,33].”
Picard, K., St‐Pierre, M., Vecchiarelli, H. A., Bordeleau, M., & Tremblay, M. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104987 · Cited by 79
Kodavanti, U. P. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.05.010 · Cited by 79
Adamo, S. A. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.10.003 · Cited by 76
“For example, stress hormones help reconfigure immune resources to enhance protection against wound infections during fight-or-flight behaviour (Dhabhar et al., 2012; Dhabhar, 2014).”
A literature review for the mechanisms of stress‐induced liver injury
Joung, J., Cho, J.-H., Kim, Y., Choi, S., & Son, C. (2019) · Brain and Behavior · doi:10.1002/brb3.1235 · Cited by 77
Exercise and adrenergic regulation of immunity
Simpson, R. J., Boßlau, T. K., Weyh, C., Niemiro, G. M., Batatinha, H., Smith, K. A., & Krüger, K. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.07.010 · Cited by 80
Gagnidze, K., Hajdarovic, K. H., Moskalenko, M., Karatsoreos, I., McEwen, B., & Bulloch, K. (2016) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1520489113 · Cited by 67
Self-citationSchiller, M., Azulay‐Debby, H., Boshnak, N., Elyahu, Y., Korin, B., Ben-Shaanan, T. L., Koren, T., Krot, M., Hakim, F., & Rolls, A. (2021) · Immunity · doi:10.1016/j.immuni.2021.04.007 · Cited by 73
Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats
Miller, D. B., Snow, S. J., Schladweiler, M. C. J., Richards, J. H., Ghio, A. J., Ledbetter, A. D., & Kodavanti, U. P. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfv331 · Cited by 71
“…inhibit inflammation (Edwards, 2012); however, numerous studies have shown that acute stress-mediated increases in corticosterone and epinephrine can stimulate leukocyte trafficking and extravasation at the site of injury in an immune cell-specific manner (Dhabhar, 2009; Dhabhar et al., 2012).”
BackgroundHe, R., Fei, W., Shen, H., Zeng, Y., & LijuanZhang (2020) · BMC Psychiatry · doi:10.1186/s12888-020-02908-2 · Cited by 71
“The generalized stress can lead to nonspecific activation of the immune system, increasing the neutrophil count and decreasing the lymphocyte count [52, 53].”
BackgroundFood restriction and chronic stress alter energy use and affect immunity in an infrequent feeder
Neuman‐Lee, L. A., Fokidis, H. B., Spence, A. R., der Walt, M. V., Smith, G. D., Durham, S. L., & French, S. S. (2015) · Functional Ecology · doi:10.1111/1365-2435.12457 · Cited by 70
“The increase in immune components, such as cytokines, causes a further increase in GCs which then acts as negative feedback on the immune system and begins immunosuppression (Dobbs et al. 1996; Dhabhar et al. 2012).”
BackgroundInfluentialFatigue in inflammatory rheumatic disorders: pathophysiological mechanisms
Korte, S. M., & Straub, R. H. (2019) · Rheumatology · doi:10.1093/rheumatology/kez413 · Cited by 71
Neural control of immune cell trafficking
Mueller, S. N. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20211604 · Cited by 72
The immunomodulatory mechanism of dexmedetomidine
Yuki, K. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107709 · Cited by 72
Conklin, Q. A., King, B. G., Zanesco, A. P., Lin, J., Hamidi, A. B., Pokorny, J. J., Álvarez-López, M. J., Cosín-Tomás, M., Huang, C., Kaliman, P., et al. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.03.003 · Cited by 66
“Lymphocyte redistribution, which can occur temporarily in response to acute stress (Dhabhar, 2011; Dhabhar et al., 2012; Rosenberger et al., 2009) may lead to ‘‘pseu do-lengthening,” whereby average TL measurements increase due to an increase in cell types having longer telomeres (Epel, 2012).”
BackgroundTurner, J. E., & Brum, P. C. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/4234765 · Cited by 66
“Subsequently, in the hours following exercise, the same e ff ector cells migrate to tissues, leaving blood to search for cells infected with viruses, bacteria, or those that have undergone a malignant transformation [55, 56].”
BackgroundAdamo, S. A. (2014) · Integrative and Comparative Biology · doi:10.1093/icb/icu005 · Cited by 71
“Various non-mutually exclusive hypotheses have been suggested as to why stress hormones alter immune function (e.g., Råberg et al. 1998; Dhabhar et al. 2012).”
BackgroundInfluentialChildhood Sexual Abuse and Indicators of Immune Activity: A Systematic Review
D'Elia, A. T., Matsuzaka, C. T., Neto, J. B. B., Mello, M. F., Juruena, M. F., & Mello, A. F. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00354 · Cited by 67
Stress and the “extended” autonomic system
Goldstein, D. S. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102889 · Cited by 76
Archie, E. A. (2013) · Parasite Immunology · doi:10.1111/pim.12048 · Cited by 66
Increased neutrophil–lymphocyte ratio in delirium: a pilot study
Egberts, A., & Mattace-Raso, F. U. S. (2017) · Clinical Interventions in Aging · doi:10.2147/cia.s137182 · Cited by 62
“In various stressful situations, the physiological response of the immune system is characterized by an increase in neutrophils and a decrease in lymphocytes.(25,26) Neutrophils play an important role in first-line defense during inflammation; once activated, they Table 1 Baseline characteristics of the study particip…”
Kotfis, K., Ślozowska, J., Safranow, K., Szylińska, A., & Listewnik, M. J. (2019) · Brain Sciences · doi:10.3390/brainsci9110308 · Cited by 64
“The non-specific immune system activation, depicted by an increase in the neutrophil count and a decrease in the lymphocyte count, may be the first line response during generalized stress, leading to an imbalance between neutrophils and lymphocytes in the peripheral circulation [41,42].”
BackgroundTargeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells
Beurel, E., Medina-Rodriguez, E. M., & Jope, R. S. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000256 · Cited by 60
“Thus, acute stress promotes leukocyte mobilization to the blood (Dhabhar et al., 2012) and infiltration into the site of inflammation (Viswanathan and Dhabhar, 2005) and mostly activates proliferative responses of immune cells (Rinner et al.”
BackgroundSpleen contributes to restraint stress induced changes in blood leukocytes distribution
Jiang, W., Li, Y., Sun, J., Li, L., Li, J.-W., Zhang, C., Huang, C., Yang, J. J., Kong, G., & Li, Z. (2017) · Scientific Reports · doi:10.1038/s41598-017-06956-9 · Cited by 66
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“Immune cells constantly traffic between the blood and various lymphoid and non-lymphoid organs and studies in rodents suggest that behavioral stress induces a significant redistribution of T cells in the body (131).”
BackgroundStress responses sculpt the insect immune system, optimizing defense in an ever-changing world
Adamo, S. A. (2016) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2016.06.005 · Cited by 64
Adrenergic and glucocorticoid receptor antagonists reduce ozone-induced lung injury and inflammation
Henriquez, A. R., Snow, S. J., Schladweiler, M. C. J., Miller, C. N., Dye, J. A., Ledbetter, A. D., Richards, J. H., Mauge-Lewis, K., McGee, M. A., & Kodavanti, U. P. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.12.006 · Cited by 61
Effect of Person-specific Biometrics in Improving Generic Stress Predictive Models
Nkurikiyeyezu, K. N., Yokokubo, A., & Lopez, G. F. (2020) · Sensors and Materials · doi:10.18494/sam.2020.2650 · Cited by 68
Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System
Liberman, A. C., Trías, E., Chagas, L. D. S., Trindade, P., Pereira, M. D. S., Refojo, D., Hedin‐Pereira, C., & Serfaty, C. A. (2018) · NeuroImmunoModulation · doi:10.1159/000494761 · Cited by 62
Metadata
- Authors
- Dhabhar, F. S., Malarkey, W. B., Neri, E., & McEwen, B. S.
- Affiliations
- Stanford Medicine (US)
- The Ohio State University (US)
- Rockefeller University (US)
- Corresponding author
- Dhabhar, Firdaus S.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 37
- Issue
- 9
- Pages
- 1345-1368
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC3412918
- OpenAlex
- W2042565214
- Cited by
- 589
- References
- 126
- Citations by year
- 2026: 45 · 2025: 38 · 2024: 46 · 2023: 52 · 2022: 53 · 2021: 69 · 2020: 50 · 2019: 51 · 2018: 36 · 2017: 34 · 2016: 38 · 2015: 33 · 2014: 27 · 2013: 13 · 2012: 4
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- The John D. & Catherine T. MacArthur Foundation
- The DeWitt Wallace Foundation Fellowship
- The Dana Foundation
- NIH (AI48995, AR46299, CA107498)
- Carl & Elizabeth Naumann Fund
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Keywords
- immune cell trafficking, norepinephrine, epinephrine, corticosterone, neutrophils, monocytes, B cells, T cells, natural killer cells, adrenalectomy, acute restraint stress, stress hormones, leukocyte mobilization, adhesion molecules, rats
- MeSH terms
- Adrenalectomy, Animals, Catecholamines, Cell Movement, Corticosterone, Epinephrine, Immune System, Leukocyte Count, Leukocytes, Male, Restraint, Physical, Stress, Physiological, Stress, Psychological, Rats, Sprague-Dawley, L-Selectin, Rats
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